April 26 10 Dosage
Regimens
May 3 Exam #2 60% To Be Scheduled
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Teaching Philosophy
Teaching is the number one priority of my Creighton mission. This is why I went to graduate school. This
is what I wanted to do all of my life. After I had graduated from pharmacy school and been a practicing
pharmacist, I applied to and was accepted into pharmacy graduate school and medical school. I chose the
former, without hesitation and without a second thought.
Availability
My students come first. I am available to students at any time. I do not have office hours. Instead, I have
a twoweek running schedule on my door which tells the student when I am not available through previous
commitments. A student may see me whenever I’m available in the office or sign up for a future
appointment on that schedule if I’m not available. When in my office, the student has my entire attention
even to the point of ignoring phone calls. I have voice mail and can return calls but a student ignored is lost
forever. Obviously, this process is only a problem when more than one student needs attention at the same
time. Thus the need for future appointments.
When asked, “What do you do?” I am reminded of a story in which the prince of a nation came upon a
construction site whereupon he asked several people what they were doing. They answered according to
their job description: “I’m cutting stone.” or “I’m mixing mortar.” The prince happened on an old stone
carver cutting a gargoyle. He asked, “What are you doing?” To which the old stone cutter replied, ”I’m
building a cathedral!” Well, I’m building competent health professionals. I teach them Creighton values. I
teach them teamwork. I teach them to be self motivated. I teach them to be self learners. We discuss
ethics; the professional, intellectual, social aspects of what it means to be a health professional graduate of
Creighton University. I tell my students that I used to teach Pharmacokinetics and Pharmacy Calculations.
Now, I use this same course content to teach Creighton values and to build competent health professionals.
It took ten years and major trauma to recognize who I am and prioritize what I do. This is what I do.!
Every morning, I get up and think, “I get to go to school today.” It’s exciting! When we talk in class about
careers, I tell the students that they will have a professional life of about 40 years. For five days a week,
fifty weeks a year, they will go to work. It had better be what they want to do! It had better be fun!
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Teaching Style – Excerpted from Presentation to American Association of
Colleges of Pharmacy – July 1997
I have over the years attempted to emulate several different styles of pedagogy in an attempt to be a better
teacher. Most of us have been trained to do research, but have we been trained to teach? Most of us teach
as we were taught. Whether that is good or bad, it’s the best we can do because it's all we know how to do.
We use the tools that we learned to pass on the skills that we learned to the next generation of health
professionals. Many of us, (Pharmacy professors) come to the AACP meeting and attend the Teacher's
Seminar. We spend one day a year attempting to perfect our craft. I say craft, for craft, it really is. It
really is a learned skill and it doesn't come on conferral of a degree. We don't know how to teach content
just because we know content. I have searched for a better way to do this. What I have found,
interestingly, comes from coaching techniques as well as pedagogical literature. Several years ago, I took
courses to become an ACEP (American Coaching Effectiveness Program) certified Judo coach. Most
states recognize this program in lieu of a teaching certificate. After taking this course, I felt that the
techniques utilized in the psychomotor domain should have counterparts in the cognitive domain and I
began to search the literature as well as attending workshops on pedagogy. I began to apply what I learned
with a gradual improvement of the outcomes of my teaching as evidenced by an improvement of overall
performance by the students and improvement of student perceptions of what was being taught as
evidenced by my teaching evaluations and student letters. A major breakthrough in my teaching style came
as a result of a one week workshop hosted by AACP in the use of case studies in teaching. What I saw was
the basics of group dynamics and the beginnings of the process described below. This seminar
significantly altered my teaching style from a professorcentered, passivelearning lecture format to an
studentcentered, activelearning problem solving format.
What I will describe is a studentcentered, active learning process applied to teaching a basic science
course. Results of this process over multiyear longitudinal retrospective study with respect to student
perceptions and performance are evaluated.
I submit that we make competent health professionals. We don't have a guild system of apprenticeship to
accomplish this, like pharmacy of a hundred and fifty years ago nor do we have a completely didactic
system, but a combination of both with a didactic system designed to impart the scientific background and
basis for the rotational “apprenticeship” experience. If, in fact, our job is to make competent health
professionals, it would be reasonable to define a competent health professional. The profession of
Pharmacy has determined that there are minimum, entry level abilities or competencies necessary for
pharmacists. It is important to understand that these are not the result of some faculty member who sits in
his ivory tower saying what he thinks is important, these are what pharmacists do. These have been
promulgated as a set competency statements. The NABPLEX competency statements are one such set.
These competency statements should be the basis for the NABLPEX part of the state board exam as well as
some of the pharmacy curriculum. They are a subset of the Creighton outcomes statements which have
been promulgated by and for the faculty. These competency statements are broken down into five general
areas and further subdivided into specific activities. These should be considered goals of the educational
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process, these measurable competencies. From these, should come the course objectives, broken down as
finely as necessary to give the student the tools to do the competencies. These objectives should consist of
three parts, information necessary to do something, (Given....), an action verb (student does something)
with a level of difficulty (Bloom's taxonomy of higher educational objectives), and what is it that is to be
done. For example:
Competence statement 2.00.00 Assessing prescriptions / medication orders and the drugs used in
dispensing them.
Specific activity 2.02.00 The candidate shall assess the physicochemical equivalency or nonequivalency of
multisource drugs
ii. The student will write (V) a professional consult using the above calculations.
It follows, then, that the practice problems and the examinations or course evaluations should be
measurement of how well the student mastered the course objectives and nothing else. If it's not an
objective, it shouldn't be graded. Conversely, if you think that it should be graded, then it should be an
objective. The exam questions and problem sets should be linked to the course objectives and the course
objectives should be linked to the competency statements. Chaining this process back one more step, it
should be obvious that the prerequisites necessary to complete the objectives also can be determined by this
process and clearly stated.
I add a fourth part: If I don't follow the above three parts and put a question on an exam which doesn't meet
the requirements, the class votes and if it is agreed that the question did not meet the requirements, it is
thrown out. Note: not that it was hard, not that you got it wrong, not that you didn't think that it should be
on the exam, but did I tell them that they needed to know how to do it?; was it an objective?; and were
there practice problems? Not all possibilities can be explored in problem sets, but general problem solving
procedures can be taught. In ten years of student suffrage, not one question has ever been voted out. I do
not believe that teaching is the hauling out of voluminous amounts of facts to be sorted out and prioritized
by the neophyte student, nor is it the spoonfeeding of predigested pabulum.
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Clearly, tell the students what they are to do.
The expectations that you should have for the student performance would be in three arenas:
These levels are really a continuum, arbitrarily partitioned into six levels with some landmarks defined. It
should be apparent that the levels should be commensurate with the student's abilities. Students should no
more be expected to perform in a previously unpracticed level than they should be able to swim when
thrown into the water for the first time. They need demonstration, practice, encouragement, practice,
evaluation, practice and then more practice.
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TABLE 2. Level of Complexity (Evans’Taxonomy of Complexity (Modified))
Cognitive Domain Psychomotor Domain
1 Overview  Highlights of the area
Simple Motor Skills: easy repetitive motions
2 Introduction: Some perspectives and Compound Motor Skills: Multiple motions not
principles necessarily repetitive
3 Perspectives and some essential principles Applied Motor Skills: care and beginnings of
dexterity required
4 Intermediate : Most essential principles and few Involved Motor skills: coordinated, multiple
topics in depth manipulations
5 Advanced: All principles and majority of topics in depth Complex Motor Skills: high degree of dexterity required
6 Most Advanced: Great depth in virtually all subjects Most Complex Motor Skills: strength, endurance,
dexterity needed
TABLE 3. Level of Mastery (Bloom’s Taxonomy of Higher Educational Objectives)
Cognitive Domain Psychomotor Domain
1 To Know, Recognize information / material Slow and awkward
2 To Comprehend, Recall information / Not as slow with moderate precision and accuracy
material
3 To Apply information, do calculations
Speed, accuracy and precision improving
technical skills but still substandard for entry level
4 To Analyze a body of knowledge identify Methodical and meeting all minimum standards of
relationships precision and accuracy
5 To Synthesize put together information in new ways
Methodical processing declining and finesse
increasing as well as accuracy and precision
6 To evaluate judge the worth of an idea Good speed, with precision
accuracy and finesse
TABLE 4. Level of Instructional Demand (Evans’Taxonomy of Instructional Demand (Modified))
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Little or no initiative required, virtually no outside class time needed
2 Moderate initiative and concentration, outside class time approaches inclass time
3 Increased level of initiative and concentration required; begin independent learning; outside class time begins
to exceed inclass time
4 Average level of initiative and concentration independent learning required; outside class time about twice in
class time
5 Substantial initiative, concentration, independent learning as well as outside class time required
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Intense initiative and concentration required, inclass time minimal
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Getting the student to buy into your expectations is critical for his/her success.
Level one in complexity, mastery and demand might be boring to a first year pharmacy student and be
considered a “nothing” course, but if your objective is to simply expose the students to the job
opportunities available to a pharmacist, for example, level one is appropriate. Setting appropriate
expectation levels is essential and making the students aware of the expectations is critical. This latter
process is most difficult. Students have a learning process which has served them well in the first two
years of undergraduate courses. In these courses the mastery level was wrote memorization (Bloom's level
I), a little essay (level II), maybe some application (Level III), and occasionally, very rarely, some analysis
(level IV). They have gotten good grades by cramming the night before the exam, which works well with
level I and decreases in effectiveness as the cognitive expectations increase. Now, in professional school,
the mastery level expectations are Level IV for many of the courses and by the time they are on rotations,
level V. Interestingly, even when these expectations are discussed in detail, the students memorize the fact
that they need to operate at level IV and are quite good at regurgitating the taxonomy, and the definitions (a
Level I cognitive skill), but complain bitterly when asked to perform at that level (do one on an exam.)
“You never showed us how to do that variation!” That’s right. If I had showed them that variation, it
wouldn’t be a Level IV. It would be a Level III.
They are not prepared to operate at these levels. They are, for the most part, devoid of experience in these
levels. They are comfortable being passive learners in which the faculty lecture and they take notes and
memorize the notes for the exam. Getting them to understand that, if they continue on this course of action,
they are doomed to failure is difficult and in many cases takes a “wake up call” of poor performance which
galvanizes them to change behavior. Those that can not, or will not because they cling to old behaviors, are
eliminated. Each year, we lose several bright, young students who can't or won’t make the transition.
Thinking is hard. Thinking is painful. To quote Tom Hanks from “A League of Their Own,” “Of course
it's hard! If it were easy, everybody could do it!”
In the first reason/excuse, I would offer that our student pool is such that we take the best of the best. At
Creighton School of Pharmacy and Allied Health Professions, we routinely have 9 applicants for every
seat. Our incoming classes GPA is > 3.2 with many having attained a Bachelor’s degree. These folks are
educable. I've found that they are neither stupid nor lazy. Content ignorant, yes, but that is why they are
here and that is fixable. Give them the tools, point them in the right direction, and get out of their way.
In the second reason/excuse, I would also offer that I routinely get students who have failed a comparable
course at other universities in my summer session. These students not only pass, but learn with enthusiasm
and get A's in a course that they hated before. And before you chalk it off to “a nothing course,” take a
look at the exams. One student from another university called me to tell me of her experience upon
returning to her home college. Her instructor asked her how she did and when she told him that she earned
an A, his response was that it must have been an easy course. What does that tell the student about his
opinion of her abilities? She whipped out the final exam and said, “Here, you do it!” His response, upon
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looking at the final was, “Oh, S!  You've got to be kidding.” This faculty member routinely fails 20% of
the class. I wonder.
In this third instance, I believe the students have motivation to perform well. They, after all, have chosen
pharmacy as their profession. In most cases, no one holds a gun to their head (although I can remember
two cases in which this was not true. Once, I had a young lady who dearly wanted to be a dancer and her
parents would pay for college only if she would become a pharmacist. She's now a dancer. A second
student didn't want to be a pharmacist but again, parental pressure. He's now a happy, professionally
satisfied pharmacist in Oregon.) If they don't want to work, we have failed to motivate them, interest them,
or show them the relevance of what we teach. In a recalcitrant few whom I am unable to motivate, even
when they complain, they recognize what is happening and complain all the way down to failure. One
student's evaluation stated, “I hated this course. I had to do it all by myself.” Right on! All learning is
active. If the only active part of the course is the night before the exam, how much can you learn,
particularly at the higher mastery levels. It has been said that people remember 10% of what they hear (I
wonder if it's that high if you are the sixth lecture of the day or right after lunch). I submit that they retain
greater than 90% of what they do, actively do, in concert with their peers.
In a few cases, students who perform poorly, do so as a result of some psychological emotional, monetary
or physical problem which must be solved before and meaningful learning can take place.
Objective: Assess (IV) differences between traditional passive and active groupbased learning
The crux of the matter is responsibility. The main difference, I believe, between active and passive
learning is shifting the responsibility for the education from the professor to the student. In the professor
centered, passive process, it's the professor's responsibility to set and adhere to a timeline. It's his/her
responsibility to “cover” the material. It becomes a game by the student to get the faculty “offtrack” so as
not to cover so much for the exam. When the students are successful, the faculty, either covers less or more
often covers the same amount, only faster. The professor assigns readings with the inevitable question, “Is
that going to be on the exam?” If you tell them it is, and it isn't, they'll never read the book again. If it is,
then you're too picky and you didn't explain it in class. Another part of the game is to ask “Is this relevant?
I don’t do this at Walgreen’s”. It's the professor's responsibility to make up the exam and the students'
game to find out what's on the exam and to argue for points after the fact. Its the professor's responsibility
to come to class prepared, give an organized, coherent lecture, and possibly answer questions. It's the
students' responsibility to take (or get from someone who came to class) a few notes which are ignored
until the night before the exam.
In the studentcentered, active learning approach, it's the student's responsibility to set and adhere to a time
line. It's the student's responsibility to cover the material. It's the student's responsibility to come to class
prepared. (You might argue that these have always been student responsibilities. I submit that in this
active learning process, they accept them and run with it and, if they don't, the members of their group
drag them kicking and screaming into compliance.) Last year's class voted for unannounced quizzes
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because they felt that there were members of the class who were not coming to class prepared. It passed
unanimously! They are given the opportunity to the set the exam schedule. From these, the faculty sets
the content and the weights. The student is given the detailed objectives, reading materials, references, and
practice problem sets. They set their own time lines to attain mastery of the objectives. From the
objectives, the faculty create the exams. This obviates the eternal question, “Will this be on the exam?”
What ever they have to do, where ever they have to go to get competent in an objective is their
responsibility. If they have to read the book, if they have to go to the reference material, if they have to
work a hundred problems, so be it. A second year student retold a first year's conversation that she
overheard, in which the first year was complaining that I had given out 90 problems to review by the
following week, to which she replied, “and you had better do them, too.”
Competence must be reached by the end of the course. I personally don't particularly care if that occurs
early or late in the course. If, for example, the class decides on two exams, then in my course, competence
of the first exam material can be shown in a special version of the second exam whereby students who have
failed to show mastery in the obtaining of the pharmacokinetic parameters from data sets must do so in
order to proceed whereas those who have shown mastery at the appropriate level are given those
parameters for their use in developing a dosage regime. If they, then, have gained competence in the first
section material, taking this exam replaces the previously unsatisfactory grade with the grade earned on
this section of the exam. If they haven't gained competence on the first section, they can not do the second
section as answers from the first section are used as input for the second section. This special exam is
required for the students who previously failed to show competence (D or F) and optional for anyone else.
Pharmacy is a lock step curriculum. What that means is that all the students take the core courses at the
same time. The corollary is also true. The whole class is off at the same time. An interesting phenomenon
has arisen in my classes. Second year students are off and in the building when the first year students are in
Pharmacy Calculations. The second year students voluntarily come into the class and work with the P1
groups and don’t need to look at the book to assist the P1s in problem solving! The third year class is off
when the second year class is in Pharmacokinetics and the same thing is happening. Competence is not that
you could do it on an exam but when you can explain it a year later!
To recap:
1. Expectations: tell them what is expected  in detail, with specific objectives and appropriate discussion
of mastery required.
2. Employ skills: Give them resources to complete the objectives (reading materials, references, problem
sets with answers.)
3. Evaluate Mastery: of those specific skills learned and objectives met.
How does a faculty do this? Group Based Learning is the key! In medicine, the era of the mad scientist,
locked up in his tower laboratory discovering the cure for Cancer or some other dreaded disease is gone
forever. Almost all significant scientific advances come as a result of teamwork. Why not teaching?
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Teaching Process  Group Based Problem Solving
In this changing world of health care, pharmacists are being challenged to enhance their clinical and
problem solving skills. Students of pharmacy must develop these skills so that they may help fulfill the
profession's emerging role in pharmaceutical care. At Creighton University students are introduced to
groupbased learning in their first professional year in Calculations and in their second year in
Pharmacokinetics in my courses and several faculty are beginning to apply this pedagogy in their courses.
Being able to work in a team, being an active, contributing member of a team is a Creighton value. It is
one of the other than content things that is stressed at Creighton University. The transformation from
traditional, didactic, professorcentered passive learning to student centered active, group based learning is
often dramatic and always traumatic  for both the student and professor! It will not go well for the first
four weeks if the student has never experienced this process. Don't give up. It will be worth every second
of agony that you go through. (I have found ways to shorten the first, troubled stages of group growth.
Constant communication and defining expectations is the key.) The first time I decided to do this, I
consulted with my chairman and told him that I was going to try a new teaching style and to be ready for a
lot of complaints and possibly bad evaluations at the end of the semester. Then I told the class how it was
to go, I held the first introduction, gave over the keys to the kingdom, and promptly when into the
bathroom and threw up! How could I turn over the responsibility for their education to children who are
always looking for the easy way out? Well, I tell you that it succeeded beyond my wildest dreams.
Seriously, it’s not for the faint hearted. It requires major shifting of paradigms on everybody’s part, but it’s
worth it if you don’t give up.
“Toto, I've a feeling we're not in Kansas anymore!”  Dorothy, Wizard of Oz.
Facilitator: Person coordinating the course. (Read Professor in other style.) Person who assists the
students upon request. S/he would direct students to references and help them organize and connect up
what they read.
Quality Team Leader (QTL): Student group leader / ombudsman to facilitator from group. (See QTL
Responsibilities at the end of this section on Teaching.)
Group: Collection of four students assigned to work together by the facilitator. Once a level of
performance is reached, they become a team.
Team: A well organized group who can work together outside of class to meet common goals.
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First day of class
Facilitator introduces the course, outlines his expectations (of both the students and the Quality Team
Leader, QTL), hands out course materials and detailed objectives. He outlines the ground rules, which
are: the groups have majority control governing number of exams to be given, exam dates, and if they
want quizzes. Items that are not negotiable are overall course time table, overall course content, number of
questions on exams, weight of exams or exchanging group members. Attendance is not optional  it's
mandatory. The group needs to be together to function.
Students are randomly assigned to groups of four by a deck of cards. Each group is a card value and each
student is a suit. e.g. the Aces are a group and each student is permanently assigned a suit. The students
are given an “icebreaker” exercise to get them to learn more about each other. Each group selects a quality
leader to serve as a direct liaison between the group and facilitator.
The students are expected to read the book and references, come to class prepared and bring the tools
necessary to work the problems; i.e. ruler, log paper, pencils, etc. They meet within their groups, discuss
the required reading, correlate the specific objectives and the reading material and begin working on
problem sets. In addition to the problem sets each individual student is responsible for several library
assignments in which they are required to calculate the pharmacokinetic parameters from the data using the
tools learned in class. The student is then required to communicate in writing the results of such
calculations with a suitable commentary regarding differences and interpretations. Each of the above
sections is designed to bring the student an understanding of the information and the processes
necessary to operate as a competent professional in the area of pharmacokinetic evaluation and
consulting. Consequently, the course evolves from a quantitative, manipulative mathematics course to
a course which stresses communication skills. Consults will be graded not only on content (the proper
dosage regimen for the patient) but also grammar, punctuation, spelling, organization and neatness. The
student may have the best medical information in the world, but if it is poorly executed, it will be
ignored.
Weekly, the students are asked to provide a one minute summary of the topic consisting answering the
following questions:
This provides a running monitor of effectiveness as well as a framework of what to stress in the reference
materials. This feedback is essential to get the mood of the groups and to address major concerns.
Furthermore it serves to provide a continuous quality improvement aspect of the course  it is constantly
evolving and refined each time it's offered. (See Weekly Status Report at the end of this section on
teaching.)
The facilitator roams around the groups to answer questions, guides groups to resources to clarify concepts
and start them on derivations of equations if needed. After each section, the facilitator will give an
executive summary of the essential material the student needs to process for the exam, if requested. It is a
short lecture (overview) designed to tie in key concepts in order to enable the student to visualize the big
picture  how small pieces fit into the larger whole. An important piece in the scenario is timing. The
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executive summary is not done at the beginning. It is not a lecture. If done before the student reads the
material, it becomes a replacement for reading the material and since it is not designed as such but designed
only to tie together the reading and emphasize salient points, the process fails. In this case, the operative
thought is: “No question is answered before it's asked.” The facilitator must wait until the student gets
stuck and needs to seek assistance. When the same question shows up in several groups, the facilitator
halts the group activity and gives the executive summary. At that point, an interesting phenomenon occurs.
As the facilitator ties things together, students are listening, the facilitator gets positive feedback by facial
expressions and head bobbing and nobody is taking notes! They are ready to hear what you have to say.
They have already created the storage space in their mind. They are not stenographers who blindly take
every word down in hopes of understanding it later. They understand it now!
Facilitator responsibilities include training the QTLs, initiating regular meetings with QTLs, helping
identify and solve problems within groups. He focuses on process, not content during the meetings. He
might intervene to clarify/correct/teach if discussion deviates too much from what is reasonable. He may
also institute changes in the course if a particular issue seems to be a major problem.
The facilitator should only intervene in a group if and only if the following conditions exist: the group is
dysfunctional; clarification, feedback, summarization, or encouragement is needed; the group needs a
formula/tool that the facilitator knows and can suggest where it can be found. Don't just give the answer.
Show them how to find it. OTHERWISE HE IS TO SIT STILL AND BE QUIET!!!!!!
The facilitator attitude must be (and perceived to be) honest, genuine, respectful, humble (here to serve, not
dominate). He must remain patient and detached, always attentive (listens to everything said, and watches
what goes on). Studies body language and gives careful attention to quiet members. He must stay at a
high energy level (groups will tend to set pace with the facilitator). He must communicate on a onetoone
basis as well as to the whole class. These must perceive that the facilitator is listening! Most students’
perceptions were favorable about the facilitator. Most students recognize that this is not an easy task:
(Student Quotes from evaluations are added in italics.)
“Dr. Makoid is an outstanding educator, he takes a tremendous amount of pride in what he does. His availability to the students
amazes me, I have never seen this.”
“I think you were very fair and extremely generous with your time.”
“I hope to get a C, but whatever my grade turns out to be I am proud of it because I know that I earned it.”
“You made a very difficult subject very easy to understand.”
“My first really relevant course and my best at Creighton so far.”
“I think he is a great teacher. Always answered my questions and encouraged the students to do their best. He also respects the
students as tomorrow’s professionals.”
However, there are some students who get very hostile about this type of learning. For example:
“This is a worthless approach  by the end of the first class I knew if I was going to get anything from it, it would come from self
teaching.!! (Isn’t this what I was trying to do?)
“We pay him to teach us, not to teach ourselves! Maybe we should of been paid, instead of him.”
“I think this is an easy way for professor’s to get out of teaching!!”
I might suggest that this is definitely not a teaching cop out. It takes considerably more effort than the
traditional didactic process. In the professorcentered, passivelearning lecture format, I would, for a 2
credit course of 100 students, give two lectures of 50 minutes each. In the studentcentered, active learning
process the students are broken into four sections of 24 each (six groups of four.) I am with those six
groups for two and a half hours each section plus an extra two hours every week that is an open section for
anyone to come and ask questions. In a session, each group of four has my entire attention for an average
of about 20 to 30 minutes. Some groups who are doing well don’t need the entire time, while other groups
need more than the average. I do, however, sit with each group for every session, listening to the
discussion and giving direction if necessary. I will also offer that active learning is not some weird process
that I thought up. There is over fifty years of competent research in the educational field proving
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conclusively that this method is substantially better for the student with significant improvement of
comprehension as well as retention. This is also apparent in data from this class at Creighton University.
The Quality Team Leaders (QTL) and the facilitator begin meeting on a regularly scheduled date and time.
They meet throughout the semester to resolve group issues and problems. The Japanese term for this is
“Kizen.” It means to continuously improve. What better way to improve than to ask the people involved,
the students, what is a barrier to your learning? Lets remove it. Last year the students voted to have
unannounced quizzes because they felt some members of the teams were not coming prepared to work. (If
I had instituted that, I’d be persona non grata. Go figure.) This year, the students suggested that we meet
in a room with tables rather than desks  done. They suggested blackboard for the groups would be useful
 a little harder, but we got it done. Westerners tend to make giant leaps and sit back on their laurels,
whereas the Japanese constantly work, constantly make things better. We want to constantly make the
learning experience better. It’s kind of like the tortoise and the hare and you know who won that race. The
quality team leaders are given instruction and reading materials regarding their responsibilities. It is their
job to make the group work. It is important to note another cultural difference at this point. It is
commonplace for Westerners to place blame when something doesn't work. Eastern philosophy is not the
least bit concerned with blame; the focus is problem solution.
It shifts from a person problem to a process problem which is completely nonjudgmental. The QTL
members bring suggestions which are discussed and voted on by the entire QTL team. If passed, it is
brought before the class and voted. If passed, it is implemented immediately. Personally, I have always
thought that student evaluations at the end of the semester have only served to allow the student to vent
his/her spleen about some thing that didn't go right in the course that the teacher doesn't know about until
it's too late to do anything about it for this class. This process allows the student to remove the barriers
from his/her learning when it will do her/him some good. Students feel that the faculty has listened and are
more responsive to listen to the faculty.
Quality Team Leader's responsibilities are to attend all the quality meetings with the facilitator or make
arrangements to have another of their group take their place if they cannot make it. They are to participate
as a group member as well as ensure that the group is functioning. The quality leader must exchange
information with the facilitator concerning problems encountered within the group so that they can be
addressed and corrected. They are responsible for the timeline between learning the material and exam
dates. They help establish and abide by guidelines given at beginning of course.
Quality Team Leader attributes include an outgoing friendly nature and a willingness to support the process
as well as a sense of personal responsibility to ensure the process is working. They must be able to
communicate verbally within the group and with facilitator and serve as a role model.
Students are to participate as a group member and teach one quarter of each exam material to their group
members. This forces each member to be an active participant or risk the wrath of their peers. Obviously,
they are to read the material, be prepared to ask and answer questions and help solve the problems. They
are to seek assistance from the facilitator when the group gets stuck.
13
It is interesting to note that some students secretly, resolutely hold on to their paradigm of the professor
centered, passivelearning process. Upon poor performance in the class, they lash out against the
facilitator, QTL, and the group even after reporting weekly to the QTL that everything is going well, the
group experience is positive and that they have no complaints. I believe that it is simply a sign of
immaturity to seek to place blame for your failures rather than to accept the consequences of your actions.
They will learn that this behavior is counter productive to their goal of becoming a competent health
professional.
14
Teaching Process  Group Growth Stages
In groupbased learning, the members must work out personal differences, find strengths on which to build,
balance commitments of this class against the demands of other classes and work, and learn how to
problem solve. Pharmacy students are competitive by nature, and in traditional didactic learning they have
relied solely on themselves. A major obstacle to overcome is to change their thinking of “me” to thinking
of “us” and to take the responsibility of teaching a portion of the material to their peers. This is an
important step in realizing that someday they may become part of a team in which they must educate other
healthcare professionals in order to improve patient care. As the team matures, members gradually learn
to cope with the emotional and group pressures they face. As a result, the group goes through fairly
predictable stages.
Stage 1: Forming
This is a stage of transition from individual to member status  like hesitant swimmers; they stand by the
pool, dabbling their toes in the water. They don't believe that this is for real. They demand a lecturer,
someone to read the book for them and tell them what to do. Their feelings may include excitement,
suspicion, fear, and anxiety about the course ahead. Student comments regarding this stage include:
“In the beginning I was apprehensive, but at the end of the class comfortable.”
“I felt very defensive at the beginning but better now.”
“In the beginning I felt intimidated, at the end of the course I felt like I could be an asset to my group.”
Because there is so much going on to distract member's attention in the beginning, the group accomplishes
little, if anything.
Stage 2: Storming
Storming is probably the most difficult stage for the group and the facilitator. It is as if the group members
jump in the water, and, thinking they are about to drown, start thrashing about. They begin to realize the
class is different and more difficult than they imagined, becoming testy, and blameful. “It's all Dr.
Makoid’s fault. If he would only teach us like he's supposed to, it would be OK!” At this stage they are
impatient about their lack of progress, but too inexperienced to know what to expect or what action the
group should be taking. At this point they resist the need to collaborate with their group and because test
time is rapidly approaching, panic and revert back to their norm  I can do this by myself  and I can wait
until two days before the exam to do it!!!!! This phase unfortunately takes place before the first exam. Do
not give in to the desire to revert back to spoon feeding the poor dears. Remember “Knowledge maketh a
bloody entrance!”
Stage 3: Norming
This stage forms rapidly after the first exam results are posted. During this stage, members reconcile
competing loyalties between themselves and their group and their responsibilities. They accept the group,
15
the ground rules, their roles in the group, and the individuality of fellow members. Emotional conflict is
reduced as previously competitive relationships become more cooperative. Group members begin to settle
down and start helping each other. The change is significant to an observer  they become more relaxed,
enjoy themselves, and begin to work together. As one insightful student wrote, “I wasn’t giving all I could
on the first exam, thinking I could pick it up days before, but I was sadly mistaken. Groups are a good
thing. I don’t think I was fully taking advantage of them, but I hope to improve in that aspect.”
Stage 4: Performing
By this stage, the group has settled its relationship and expectations. The team is now an effective, cohesive
unit. You can tell when the students reach this stage because they get a lot of work done. Complaints are
rarely made. In fact, when asked to give their group mates a percentage score based on their group activity
 everyone unanimously gives their group members a 100%!!! They have moved from passive to active
learning. One student's response to the facilitator's question of “How are you doing?” was “We’re busy.
We’ll call you if we have any questions.” You can tell when you are there. No questions!
At this stage they may also have insights into personal and group processes, and a better understanding of
each other's strengths and weaknesses. For instance, when surveyed, a majority of students stated that their
greatest individual weakness was that they felt they were slow to understand/learn. They perceived that the
group’s major weakness was that they could not meet as much as they wanted to outside of class.
COMMUNICATION
“I know you believe that you understand what I said, but I'm not sure you realize that what you heard is not what I meant”
1. “In the beginning I was apprehensive, but at the end of the class comfortable.”
2. “I wasn’t giving all I could on the first exam, thinking I could pick it up days before, but I was sadly mistaken. Groups are a good
thing. I don’t think I was fully taking advantage of them, but I hope to improve in that aspect.”
3. “I felt very defensive at the beginning but better now.”
4. “I'm busy. I'll call you if I have any questions.”
5. “In the beginning I felt intimidated, at the end of the course I felt like I could be an asset to my group.”
6. “It's all Dr. Makoid’s fault. If he would only teach us like he's supposed to, it would be OK!”
7. “I was very skeptical concerning the teaching method, especially at the beginning.”
8. “Working in groups was definitely beneficial. I think I learned a lot more than I would have learned on my own.”
9. “I felt the course taught me to think more on my own.”
10. “We pay him to teach us! Not us teaching ourselves! Maybe we should have been paid instead of him!”
11. “Working in groups helped me get a better understanding for it because when I talked about it, I found I really knew what I was
doing. I think it was good just the way we did it.”
12. “Our group has hard time going at the same pace. Some members are ready to jump into the problems with no idea about the
concept while others try to read up on it because they don’t understand.”
13. “The group thing needs a lot of work.”
16
Barriers to Overcome
1. Physical
A. This method of instruction will not work well in lecture amphitheaters. Even in rooms with separated
desks, this does not work well. Students complain there is not enough desk top space, and they are
distracted by other groups talking. The ideal atmosphere includes a room divided into discrete sections for
each group with a large table and blackboard for each section.
B. In retrospect, a common complaint of spring/fall semester students is that they don’t have enough time
to work together. This method of teaching is not well suited to 50 minute periods. The ideal scenario
seems to be blocks of time  for instance, summer groups seem to coalesce faster because they meet for 3
hours per day. They have time to accomplish problem sets without running out of time.
A. Student Attitude  What I call the John Wayne attitude: I can do it all the night before and teacher will
tell me everything I need to know for the test among others.
B. Facilitator Attitude  You just got to believe and exude confidence in this style of learning. If you
don’t, it will crash and burn.
3. Materials
A. Objectives must be and perceived to be clearly stated and detailed. Approximately 95% of students
surveyed agreed that they felt the course objectives were clearly stated. In addition, 98% agreed that the
examinations given reflected the course objectives.
B. Content of the class must be organized in a stepbystep fashion so that the student is always building
his knowledge base.
“Paradigms are significant problems that cannot be solved with the same level of thinking with which we
created them” EINSTEIN
It is possible to facilitate the group growth into stage four if the students are told what to expect about the
process as well as monitored and behavior corrected as it develops.
17
Teaching  Student Perceptions of the Process
Objective: Discuss (III) the student perceptions and corresponding supportive data derived from
group based learning experience
What to expect:
Expect variability in the classroom. In traditional didactic lecturing, the classroom remains a static
environment, however in group based learning each class becomes a new adventure in teaching. Each
group progresses at a different rate and has unique characteristics.
Expect that the groups may fail in the beginning and be ready to accept their failure. It is extremely gut
wrenching to watch this, but a valuable lesson is learned after the exam: “Let's start working together!”
Expect that the groups will no longer need you when they approach Stage 4. It can be very disconcerting
for a facilitator who wants to be needed!
Expect that other faculty may consider group based learning after they come to observe the process.
However, expect also that some may run away as fast as they can!
With respect to the students expect better performance, higher grades, greater retention, improved attitude
toward field, improved attitude toward facilitator.
18
Teaching  Supportive data  Student Performance
Group work outside class increases prior to the night before exam. This can be readily observed and
substantiated by the fact that the students who do not work within a group environment or groups that do
not meet outside of class time do not perform well on exams. This is supported by student comments and
selfevaluations.
TABLE 5. Supportive data  Exam Scores
Passive Learning Group Active Learning Group
1991 – 1993 1994  1996
(n =273) (n = 255)
Exam 1 78.6 85.3
Exam 2 82.2 92.7
On the average, exam means increased one letter grade without any change in content, complexity or
mastery requirements.
“This was the first time that I went to bed at 9:00 P.M. the night before an exam.”
19
Teaching  Supportive Data  Student Perceptions
TABLE 6. Student Perceptions of their performance
Exam 1 Exam 2
Higher 27% 57%
Same 14% 11%
Lower 21% 11%
No Reply 38% 21%
Since most students do not have a comparison between how they would have performed in a traditional
pharmacokinetics course in comparison the groupbased course, they have difficulty in perceiving how the
group has affected their grade. There are, however, a few students from other universities who have had
the “opportunity” to experience similar courses differing only in active v passive style. At first, they are
apprehensive and try to do it the passive way. They even tell me that at _____ university, we did it by
passive teaching style (my translation). I tell them that the operative definition of insanity is to do the same
thing over again and expect a different result. I ask them to give this process a chance and to try something
new.
It was interesting to compare IDEA evaluation responses for traditional (passive) students versus group
based (active) students. In both subject matter mastery and the development of general skills, students who
took the traditional course in the summer mirrored group based learning responses. It has long been my
perception that the summer classes performed better than the regular semester. Everything I did was the
same in both classes, so the differences were not something that I did. In 1991 through 1993, I observed
that in the summer, students came to me in groups to answer questions while in the regular semester, they
came singly. Voluntary group learning was the only difference! Thus, in the subsequent tables, Passive
Summer is separated from Passive Semester. It can be seen that Passive Summer Session more closely
resembles the active groups because they, in fact, voluntarily formed active study groups.
TABLE 7. Student Perceptions from IDEA Evaluations Regarding Development of General Skills
1 3 4 5
Strongly 2 Neutral Agree Strongly
Disagree Disagree Agree
20
TABLE 8. Student Perception from IDEA Evaluations of Questions regarding Subject Matter
Mastery
1 3 4 5
Strongly 2 Neutral Agree Strongly
Disagree Disagree Agree
TABLE 9. Student Perceptions from IDEA Evaluations Regarding Development of Personal Skills
1 3 4 5
Strongly 2 Neutral Agree Strongly
Disagree Disagree Agree
It is not surprising that the students perceive an increase in personal responsibility in group based learning.
When asked if the group experience made them a more responsible and knowledgeable group member,
>95% agreed. In reply to the question of what was your group’s greatest strength, a majority of students
replied that their group worked well together  members were willing to help each other, communication
was good, and they worked hard to accomplish the given objectives. When asked what strengths they
gained through the group experience, the students replied: understanding, confidence, communication
skills, time management, listening to others.
TABLE 10. Student Perceptions from IDEA Evaluations Regarding Student’s Self Rating
1 3 4 5
Strongly 2 Neutral Agree Strongly
Disagree Disagree Agree
Student comments:
“After taking this Pharmacokinetics course, I have a more confident feeling about going into the pharmacy profession. I feel that I am
competent and secure in deciding what's best for a patient in regards to dosing regimens.”
“Would like to take advanced kinetics class  am very interested in the field.”
“I was not looking forward to taking this course, however, I have gotten more from this class than I ever thought I could have. I
actually enjoyed kinetics, the method in which the course was taught, and then being able to solve the problems. I now have a very
positive attitude toward kinetics and look forward to taking another class.”
21
Teaching  Appendix A  QTL Responsibilities
Congratulations! You have volunteered (or have been coerced) to assume the role of a Quality Team
Leader (QTL). This is a position of leadership within your group and with it comes some added
responsibility. The purpose of this handout is to outline your role as QTL  your duties, and the
expectations I have for you. Do not panic. I realize that for most of you this process is new and different.
Group based learning is rapidly becoming the teaching method of choice for several important reasons 
students understand better and retain longer knowledge that they have actively learned, and they usually
perform at a higher grade level. The main difficulty students have with this type of education is that they
have never been responsible for learning or teaching each other within a group environment. Many
students resist group learning and rebel or they may not know how or where to begin. Another obstacle is
establishing and maintaining a timetable in order to get through the material before the exams. A major
dilemma you face will be focusing the group’s energy and attention to work through concepts and problems
in time for the exams.
QTL Responsibilities:
1. Attend all quality meetings or make arrangements to have another group member take your place if
you cannot make it. This is important to keep lines of communication open between each group and me.
You can voice your group’s concerns, bring suggestions to discuss and vote for changes. You will be
responsible to take back meeting information to your group.
2. You are to participate as a group member  being a QTL does not excuse you from taking on your
share of group responsibility. Set an example to come to class with the required materials and be ready to
work.
3. Be a role model  be willing to support the process. Your fellow group members will take their cues
from you. We all know attitudes can be as infectious as the common cold  Keep yours positive! If you
have concerns or feel yourself down, talk with me.
4. Communicate with me about any problems or concerns within your group. This is not “ratting” on
your peers. Our (mine and yours) major concern is to ensure that the groups are functioning to the best of
their abilities, that they are meshing together, learning the material, and working on the problem sets. If
your group (or a particular member) is not functioning well, everyone loses time and knowledge. My job
as facilitator is to help get the group working  BUT this can only happen if I know that a problem exists.
This information will remain between us and confidential.
5. You will be responsible for creating your group’s timeline for learning each portion of material
before the exam. Your class determines the date and time of exams but the content is not negotiable. You
need to work within your group to establish how much time you need to devote to each portion so that your
group will be done with the material before each section exam. You will have to monitor your group’s
progress and keep them focused. Tell them what is to be covered next, assign problems to members, and
keep moving forward. Not all groups will work at the same speed. What is important that all the
designated material is covered well before the exam  Do not wait to learn it all the last 2 days before the
exam! It won’t happen!
6. You are responsible for turning in a weekly status report. It is important for us to communicate both
verbally and in writing. I need to know how everyone is progressing through the course material and
within the group. If you have any concerns/problems that you feel cannot be addressed in the quality
meetings, write them down on this report.
22
Teaching  Appendix B  QTL Weekly Status Report
MEMBERS PRESENT:_________________________________________________
MEMBERS ABSENT:__________________________________________________
The purpose of this weekly status report is to keep the lines of communication open between you, the QTL
and me, the course facilitator. Honest, open and constructive dialogue (written or verbal) between us will
result in a class which is continuously improving.
23
Teaching  Appendix C  Examples of QTL Communications:
QTL Meeting 1
I. Introductions:
II. Importance of Group Based Learning(GBL): Pharmacy classes currently using some form of GBL
are: OTC, Toxicology, Therapeutics, Pharmacokinetics, Pharmacology, Chemical Basis for Drug Action,
Parenterals and the list keeps growing… .. However, the main difference between the above classes and
this class is that we teach and monitor the group process along with the content. Past experience has found
that in group based learning, the content cannot be mastered if the group process is failing  course
performance is directly tied to group performance. Therefore, it is imperative that you learn principles of
group dynamics along with the course content. These skills will last you a lifetime and work in any group
situation you may find yourself. Remember as a future pharmacist, you will be a member of the health
care team  and it is necessary to work effectively with others (physicians, nurses, lab, xray, etc.) to solve
patient problems.
III. Peer assessment: In group based learning, you have an opportunity to observe your peers in a close
problemsolving environment. You will have more detailed insight and knowledge of their work than the
instructor. In order to honestly and effectively evaluate everyone’s performance within the group, peer
assessment is necessary. In your future as a pharmacist, you may be asked to fill out a performance
appraisal on a coworker. Many pharmacists find this upsetting since they have had no prior experience at
doing this. We must get comfortable with the process of receiving and giving assessment feedback. In this
class, peer assessment will be worth 10% of your final exam grade. You will assess yourself and be
assessed by your peers at midterm and at the end of the course. Only the final peer and self assessment will
count towards your final grade. The midterm assessment is for practice and your own personal growth.
See attached sample copy.
IV. Group dynamics  problems?
V. Decision making: Any group’s goal should be to reach a decision that best reflects the thinking of all
group members. This is called reaching a consensus. A consensus is finding a proposal acceptable enough
so that all members can support it and no member opposes it. A consensus is neither a unanimous vote  a
consensus may not represent everyone’s first priorities nor a majority vote  (in a majority vote, only the
majority gets something they are happy with; people in the minority get something they don’t want at all).
A consensus requires time, active participation of all group members, skills in communication (such as
listening, conflict resolution, and discussion), creative thinking and openmindedness.
Rules for Decision by Consensus:
• Look for acceptable alternatives
• State your opinion  it doesn’t matter that others do not share it. Conflict spawns creativity.
• Look for winwin situations
• Remember that difference of opinion is healthy
Aiming for consensus requires a much different strategy than does unanimous or majority vote. To reach a
consensus, the group must let each member voice their concerns/opinions. It may be hard to tell when you
have reached consensus  a good rule of thumb is when no one is completely satisfied, but the decision is
one that you all can live with. Complete unanimity is not the goal  it is rarely achieved, but acceptance is.
VI. Timelines:
How to deal with “floundering” (a lack of direction):
• Review the timeline within the group. Hopefully by this point you have set dates for exams and know
the topics to be covered for each. Draw the timeline out on paper. Give each member a copy. Assign
problems to individuals and keep track.
• State “Let’s review our timeline and make sure it is clear to everyone.”
• “What do we have to do next?”
• “What do we need to do/ask so we can move on? What is holding us up?”
• Finish up every class by giving everyone duties for the next meeting. There should not be any
confusion at that point as to who is responsible for what.
24
Teaching Appendix D –
25
Teaching Appendix E  MANAGING DIFFICULT PEOPLE
Just about everyone has felt the pulsepounding, faceflushing, wordsputtering frustration caused by trying to reason with
difficult people. We find them to be uncooperative, uncompromising, and stubborn. Each encounter with them leaves us
feeling increasingly frustrated and angry. No matter what we do, it isn't effective. While it may seem easier to ignore
difficult people rather than face a confrontation, team morale and productivity greatly decrease when difficult people are
tolerated, even reluctantly. The following five strategies allow you to take control of situations involving difficult people and
build more cohesive teams as a result.
Question: can you find yourself  what type are you?
STRATEGY 1: Depersonalize the situation
No matter how challenging, belligerent, or negative the difficult person behaves, do not take it personally. Difficult
people are often acting out their personal problems, and their behavior is a cry for help. You can more easily control your
emotional reactions to them and defuse any anger you feel if you do not take their behavior personally. When you
encounter a difficult person, observe how he or she behaves with others, especially other team members. You will find
that the behavior is consistently difficult. This awareness helps put things in perspective; you can see that you are not to
blame for the difficulty.
STRATEGY 2: Learn to identify difficult personalities
Generally, there are seven types of difficult personalities. As each type is presented, strategies for coaching, motivating,
and communicating with them will be presented. It takes some planning and practice, but as we learn to manage these
difficult types, the effectiveness of the entire team will increase.
ATTACKERS: Attackers are hostile, aggressive, abusive, and intimidating. They need to be right and will charge like
angry bulls if they think they have been challenged or crossed. The best coping strategy is to let them blow off steam and
express their anger in a safe environment. But you can't let them run on. To maintain control, address them by name:
“David, I hear what you are saying. Let's sit down and talk about it.”Getting attackers to sit will have a calming effect on
them; and, once calmed, attackers become more reasonable. Take what attackers say seriously. Hear them out, let them
know you have heard them, and then state your position clearly and avoid the temptation to argue.
EGOTISTS: Egotists are often experts and know more than others on the team about a particular subject. They believe
facts are power; and, since they know the facts, they act in a superior way that often demeans the knowledge of others.
Plan meetings so the egotists on the team speak first and allow time for them to “bask” in their knowledge. This strategy
minimizes their tendency to interrupt later in the meeting. You must be prepared with facts and information, because you
cannot “fake it” with egotists. But you can capitalize on what they know by asking questions. Egotists love to show off and
have their knowledge appreciated. If you approach them from this perspective, their abusive attitudes and behaviors can
be tempered so you can more effectively use their knowledge and expertise to support your efforts.
SNEAKS: Sneaks take potshots. They undercut your authority in devious ways by using sarcasm, which is often
disguised as a joke. Never ignore the sneak's snide comments. That just gives them power to continue Instead, expose
them. When they snipe at someone, be direct and ask them for their opinions or solutions. Force them into the open and
you will weaken their ability to cause problems. Try to turn their attention and comments to the issues, not the
personalities involved. Once they realize you won't put up with their sniping, they will stop.
VICTIMS: Victims see everything negatively. They complain, whine, seem to be powerless, and act defeated. Victims also
shift blame and refuse to take responsibility for situations or decisions, especially unpopular ones. They act as if they are
passing on orders from above and blame the boss for that “dumb” new policy. Such behavior hurts morale and erodes the
support of your team. Since victims often believe no one thinks they are important or takes them seriously, start your
interactions by listening to what they say. Steer them toward the facts, which are usually much less negative than their
interpretations. When you ask for suggestions to improve the situation, maintain control by bringing up the negatives
yourself, then dismiss each logically. Direct their attention to the more positive aspects of the situation.
NEGATORS: Victims seem pale compared to true negators. Negators aren’t just negative, they distrust anyone in power.
They believe that their way is the only right way, and their motto is “I told you so.”Stay positive, but realistic. Delay
discussing solutions, since negators will dismiss every solution as soon as it is spoken. Refuse to argue with them and
stick with the facts. Anticipate any objections they may raise and prepare facts and information to refute them.
SUPERAGREEABLE PEOPLE: While superagreeable people are easy to like, they are one of the most difficult
personalities to deal with. Superagreeables are outgoing and friendly; but, because they have such a strong need to be
liked, they frequently become whatever others need them to be at the expense of their own needs and desires. They are
usually terrified of making mistakes. Superagreeable people can’t say “No” and, thus, overcommit themselves and their
staffs. They disappoint and frustrate the very people from whom they so desperately need to receive approval— their
managers, staff, coworkers and, in personal matters, their family and friends. Carefully limit how much you ask of them to
eliminate the disappointments caused by missed deadlines.Teach them to see things in greater perspective to help them
overcome their fear of making mistakes.
26
UNRESPONSIVE PEOPLE: Unresponsive people are the ''clams'' of humankind. They are the most difficult personalities
to deal with. They don't reveal their true motives, and you play a guessing game trying to find out what makes them tick.
They are hard to understand and seemingly impossible to draw out. Yet that is the most effective strategy: draw them out.
Always ask openended questions that require more than “Yes” or “No” answers, then wait for them to respond. Typically,
they respond more slowly than other kinds of personalities and rely on others to take over so they can maintain their clam
like reserves. Even if the silence between you and an unresponsive person grows chasmlike, wait for a response. If they
refuse to open up, agree to meet again later and ask them to think about specific topics you will discuss at that time. This
strategy will eventually draw them outand, once they begin to trust you, they will become less clamlike.
List the difficult people you work with and identify which personality most closely fits their dominant behaviors. Jot the
techniques for each personality on a 3 x 5 index card and review the cards before meeting with them. Take time to review
the strategies for dealing with a particular personality, and then recall a past unsatisfactory confrontation with him or her.
Imagine how much more successful it would have been if you had used the techniques for dealing with that personality.
Now, visualize your next confrontation with that person and see yourself Using these techniques. Rehearse until you feel
comfortable with the techniques and are well prepared to deal with the person who manifests this difficult personality trait.
(Manning, Marilyn Ph.D. and P.A. Haddock. “Managing Difficult People,” SKY, November 1988, pp. 128135)
27
F I R S T E D I T I O N
Basic Pharmacokinetics
Omaha, Nebraska
Omaha, Nebraska
ISBN 00000000000
ABCDEFGHIJDO89
When I first started teaching, I had the good fortune to work with another new
Ph.D., John Cobby. We struggled through our first five years on the otherside of
the podium together and learned many of the tenents upon which this book is
based, not content but process. First and formost, it was his belief that students are
bright, enthusiastic and hardworking. We should tell them what to do and get out
of their way. We both prepared extensive handouts complete with even more
extensive practice problems so that the student could experience the scientific
method as a detective might solve a murder mystery. The idea was to make learn
ing pharmaceutical science interesting and fun. Through the years, as the methods
became more refined, student perceptions and performance improved dramatically.
OBJECTIVES
At the completion of this chapter, the successful student shall be able to:
1. define pharmacokinetics
2. state the overall objectives of the course
3. state the major themes of the course
4. state the course organizational structure with respect to study sections
5. state the objectives of each study section
6. state the examination structure and objectives
7. state student performance expectations
8. state the schedule and timeline
Each major theme of the course is further broken down into study sections, each
with their own set of general objectives as shown below:
F. Bioavailability objectives:
1. Given sufficient data to compare an oral product with another oral product or an IV prod
uct, the student will estimate (III) the bioavailability (compare AUCs) and judge (VI) pro
fessional acceptance of the product with regard to bioequivalence (evaluate (VI) AUC, T p
and ( C p )max ).
2. The student will write (V) a professional consult using the above calculations.
H. Clearance objectives:
1. Given patient information regarding organ function, the student will calculate (III)
changes in clearance and other pharmacokinetic parameters inherent in compromised
patients.
1.3 Exams
How are the exams Exams will consist of problems which will be linked directly back to an objective
made? (above) and a library assignment in which you will be asked to evaluate a research
article with the tools available to you by the time of the exam as discussed below.
First Exam
What content should I IV Bolus Parent compound 50 pts
look for in the paper and IV Bolus Parent metabolite 65 pts
what is its relative
IV Infusion 65 pts
worth?
Pharmacological Response 75 pts
Oral Dosing / Bioavailability 50 pts
2. Include a Xerox copy of the entire paper. I need to evaluate it, too.
3. Enlarge the graph by successive Xeroxes so that you can accurately evalu
ate the data.
VI. To Evaluate: means to be able to judge the worth of an idea, form hypothe
ses and do problem solving, research, invent new knowledge. (This is the doctoral
level of participation in the area).
Can’t I just do it the A professional routinely operates at level IV and V with occasional forays into
same way that I have level VI. This is where you will operate in this course and in most subsequent
always studied? courses in the professional curriculum. You will note that each of the objectives for
the course contains specific action words followed by the level in the taxonomy at
which you will operate. These are the standard descriptive terms for use in instruc
tional objectives. You will be asked to do critical thinking, not simply recite or
recognize the right answer. Problems challenge thinking skills and demand the
synthesis of material into concepts. To facilitate this transition we both must work
very hard.
What must I do in this 5. Facilitate Learning. You received objectives (above) and a summary for
active learning process? each study section (chapters in this text), of exactly what is expected of you with
You MUST participate in examples in the problem sets at the end of each chapter. We will have ample time
class and in your
assigned groups!!!
during class to field questions generated by the correlated reading and problem
sets, as well as homework assignments. I will not be duplicating any book’s efforts.
Student participation in class is required. You will answer (as well as ask) ques
tions, do problems in class. You will sound things out and get feedback from me
and your fellow colleagues. Remember  the class is to help you learn. It is not the
sole means of learning, nor am I the source of all knowledge. Its’ only reason for
being is to help you organize and summarize what you learn. It has a relatively
simple plan with multiple examples. From these examples you will develop con
cepts which will obviate the need for memorizing individual facts (or actually me
entirely). I will assist you in the formation of these concepts. It is patently obvious
that I can not give you every possible example of every type of question that you
will be asked during your professional career. For one thing I don't know what
questions you will be asked nor problems you will encounter. Going from the spe
cific to the general forms concepts which will allow you to go from the general to
the specific, even if you have never been there before. The total medical knowl
edge is now doubling at a rate of every 4 years. I can not teach you the content nec
essary to operate 5 years in the future, let alone 40. You must learn to learn.
Hence, if you plan to become a competent professional, you must operate at least
in Bloom's level V.
How do I get in touch 6. Be available: I do not have office hours. I believe them to be restrictive
with the teacher? from your view point. What I do have is a schedule calandar preparede weeks in
advance of when I am NOT available. You may set an appointment, at least a 1/2
day in advance to guarantee that I see it, any other time. Of course, appointments
are not necessary if I'm in my office, but you take the chance of my not being there
or someone else being there ahead of you if you do not sign up. You may contact
me by email: makoid@creighton.edu, or by phone: 4022802952. You may also
contact my secretary, Dawn Trojanowski in the departmental office or by phone
4022802893 to make an appointment.
How can I tell the 7. Be responsive: Each day, you will be asked to provide me with a one
teacher how things are minute summary of the topic consisting answering the following questions:
going?
a. What was the main thrust of the study section (What did you read)?
b. What was clear about the study section? What was done well?
c. What was unclear? How could it be done better?
Do I have any say in the After each exam, in addition to working out the problems, we will decide whether
examination questions? any individual question was not covered by the objectives. Note: Not that it was
tough, not that you got it wrong, not that it didn’t allow you to tell me what you
knew, but did I tell you that I was going to ask you to do it? (Was it covered by the
objectives?)
How are the exams 8) Evaluate your performance fairly and honestly: Quite simply, I’m going to tell
graded? you what I expect that you will do. I will show you how to do it. I will provide you
with practice in doing it. I will provide you with an exam which tests your ability
to do it. The exams, as well as the whole course, will use real data and/or pharma
cokinetic parameters for real drugs in real patient settings, much like the state
board exams (and hopefully real life). Like both of these situations, all answers are
interconnected. What that means is, if you improperly calculate a parameter which
is needed to make another calculation which is used to make a third, etc. ALL are
wrong. Conversely, if you can’t get a particular calculation by one method or equa
tion, try another. That’s simply the way it is. You probably wouldn’t get much sym
pathy if you calculated a dosage regimen properly based on a wrong elimination
rate constant and ended up killing your patient.
You Will:
What do I have to do? 1) Come prepared to participate in class. This is your full time job. If you are
How much work is really working full time, it is usually 40 to 60 hours per week. If you go to college 15 to
expected? 18 credits and prepare/study 2 hours for each credit, you work 45 to 55 hour per
week  you have a full time job. Your commitment is the 45 to 50 hour week not
just the contact hours and a night for each exam. This specifically means for each 1
hour class, I expect no less than 2 hours of preparation on your part. Each of you
will be assigned to a study group. You will work the problems together and teach
each other both in and out of class. We will have group discussion of class as well
as group problem solving. It will be your responsibility that every member of
your group be adequately prepared to answer for the group during recitation. There
will be a grade for group participation. Part of your grade will be based on your
peer evaluation.
Do I have to read the 2) Read the text. When you read, read critically. Do you understand each idea?
text? Each page in the HTML version has an evaluation section. If you get it you will be
asked to be a resource for that page for your peers. If you don’t get it, you will be
directed to your peers to seek help. Come prepared to ask about it in class.
Why do I have to do the 3) Work the problems. Check the answers. These come from old exams, so they
problem sets? are the type that you are likely to see. Work them in your study groups so that
everyone can see your thought processes. Bring them to class if you can not do
them or come and see me privately. Be prepared to show me your attempts at solv
ing the problem. I will show you how to get started and give direction to your
thought. I will not work the problem for you. You would not learn if I did it for
you. It is crucial that you work the problems. Each has a specific objective. Over
all, they contribute to your gaining facility in the processes that a pharmacokineti
cist must know how to do.
Can I just coast 4) Do not delude yourself with respect to your performance. If you received a
through? grade that was less than satisfactory for you, do not simply console yourself by
saying “I knew the stuff, I just made a little error.” Can you get it right consis
tently? That's when you know the stuff. That is not a laudable goal. That's what a
professional does. There have been several students in the past that “knew that
stuff” right up till the time that they had to repeat the course (and sometimes
beyond).
In addition to the above course objectives, there are specific objectives for the use
of computers in the course. They are:
What will I be expected • Simulation. The student will be able to utilize appropriate graphs and histograms used classical
to do with the comput pharmacokinetics in the course. The student will demonstrate effects of changes in pharmacoki
ers? netic parameters on the ADME processes and correlated pharmacological / therapeutic
response.
• Graphical Solutions. Many thing become more understandable in graphical form, or at least we
are able to predict what would happen if a trend were to continue.
• Numerical solutions. The computer would accurately and repeatedly calculate convoluted, diffi
cult equations quickly and easily.
These objectives will be met in a variety of ways. Clearly, the most direct method
is the solution of the problem sets by computer. First, I expect that you would do
the problem by hand, complete with graphs and other supporting calculations fol
lowed by computer simulation and data analysis. Just how close did you come to
the best fit? Next, a portion of each exam will be a library exercise in which you
will find and evaluate a published article according to the principles that you
learned in class utilizing the computer facilities. How close did you come the
authors numbers? Do you, in fact, even agree with the authors? You will prepare a
short consult in which you describe the patient and what the authors did along with
your support (or nonsupport) of the authors conclusions.
2. You will also need 2 cycle semilog paper and a clear straight edge ruler for
use in class. These are available in the book store or at an office supply store. You
can also downoad a copy of graph paper printer for you own personal use. A copy
is available in the computer lab.
4. You will need a 3” D threering binder for collecting and maintaining all
the pages in this book as well as your class notes.
What do I need to do in Work in your study groups. You never learn it so well as when you teach it to
and out of class? someone else. Everyone benefits from a well run prepared study group. You are
not in competition with your fellow classmates. If everyone earns an “A”, then
everyone will receive one.
How can I organize this Organize and label your study notes. This is basic survival. This is one strategy
material? that I find works well. I recommend it highly. Good study notes are formatted on
looseleaf in a three ring binder. The individual pages have a line drawn down
about 1/3 the way in. The notes are taken on the right (2/3) of the page, while
labels go in the left. The labels on the left are often written as questions, which are
answered in the text on the right. Loose leaf binders allow for the incorporation of
reading summaries as well as relevant problems and homework to be organized
with a divider all in one place. You should write intelligently, with proper punctua
tion and spelling as if you were preparing a consult for a physician. Organization is
the key.
Remember: you may have all the information in the world at your fingertips; be
able to solve the most difficult therapy problem and no one will listen to you if you
can't communicate intelligently. You will be required to communicate in this
course utilizing both written and verbal skills.
TABLE 41
Exam 1 410
Exam 1 grp/ind 40
Library 1 5075
Exam 2 410
Exam 2 grp/ind 40
Library 2 50 to 75
Total 1000 to 1050
Group Bonus 50 to +50
Group Total 950 to 1100
You will be require to pass the first exam before you are allowed to take the
second.
2. At the next higher level, I will guarantee that if you comprehend this mate
rial at level V, you will have no trouble passing any state board anywhere with
regard to pharmacokinetics.
3. You will gain a useful skill that will make you an integral part of the health
care team.
Do I really need a 4 You will learn to learn. There is an old proverb which goes: “Give a man a
teacher to learn? fish and you feed him for a day. Teach a man to fish and you feed him for a life
time.” The B.S. Degree is designed to eliminate teachers. An educated man is one
who has learned to how to learn, not one who memorized a page in a book. That
is what you need to be a professional. The total medical knowledge is doubling at a
rate of every 34 years. That means that you will be out of date shortly after gradu
ation (if not before) if you simply memorized content and don't learn to learn and
continue to learn throughout your career.
What about cheating? One last piece of information: Neither you nor I will not tolerate any academic
misconduct. Anyone caught will minimally receive an “F” for their efforts and I
will recommend dismissal from the program. The profession has no room for
unprofessional behavior. I will prosecute.
B: Math review
1. Numbers and exponents
2. Graphs and reaction order
3. Calculus
4. Laplace transform
5. Computer Introduction
6. Computer simulation and problem sets
C: Pharmacokinetic modeling
1. What a model is and what it isn’t.
2. Why we model
3. Philosophy of modeling
D: Pharmacological Response
1. Michaelis  Menton Mass balance equation
2. Interrelationships between Concentration, time and response.
e. Professional communication.
2. Metabolite
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Rate vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
F: I.V. infusion
1. Parent compound
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets
e. Professional communication.
1. Metabolite
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets
e. Professional communication.
G: Biopharmaceutical factors
1. Absorption
I. Physiology
II. Mechanisms
H: Oral dosing
1. Parent compound
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets
e. Professional communication.
2. Metabolite
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II. Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets
e. Professional communication.
I: Bioavailability, Bioequivalence, Drug product selection
1. Relative and Absolute Bioavailability
2. Factors Influencing Bioavailability
3. Methods of Assessing Bioavailability
I. in vivo
II. in vitro
III. Correlation
4. Bioequivalence
5. Bioavailability
6. Drug Product Selection
L. Clearance objectives:
1. Given patient information regarding organ function, the student will calculate (III)
changes in clearance and other pharmacokinetic parameters inherent in compromised
patients.
2.00.00 Assessing prescriptions/ medication orders and the drugs used in dispensing them,
1.04.00Given a prescription or medication order, the candidate shall identify or explain the rationale for the
dosage regimen.
1.04.03The candidate shall calculate the dose or rate of administration of a drug when given appropriate data.
2.00.00 Assessing Prescriptions/Medication Orders and the Drugs Used in Dispensing Them
2.01.00 The candidate shall identify, interpret, or explain patient or pharmacokinetic factors that affect either the
efficacy or safety of individual drug therapy.
2.01.01The candidate shall relate the influence of patient factors (e.g., age, weight, sex, occupation, compli
ance, exercise, stress, placebo effect, vital organ function) to the choice or dosage of drug therapy.
2.01.02 The candidate shall explain or apply biopharmaceutical principles or pharmacokinetic factors (e.g.,
absorption, distribution, metabolism, excretion) as they relate to dosage regimen design or evaluation of experi
mental or patient data, including the: definition or explanation of biopharmaceutical terminology; recognition of
the effects of patient health status or concurrent drug therapy on bioavailability; determination of pharmacokinetic
parameters or dosing regimens (e.g., loading dose estimations, maintenance dose calculation, elimination half
life, determinations of clearance, or volume of distribution); or recognition of biosocial factors that affect pharma
cokinetic parameters (e.g., smoking, alcohol consumption, work environment.
2.03.00 Given appropriate information or data regarding bioavailability, the candidate shall demonstrate proper
judgment to assure safe and effective drug therapy.
2.03.01The candidate shall interpret or utilize in vitro dissolution test results that are used to predict bioequiv
alence or shall distinguish these from in vivo tests.
2.03.02 The candidate shall differentiate between relative and absolute bioavailability.
2.03.03 The candidate shall interpret area under plasma concentration versus time curves as an assessment
of bioavailability.
2.03.04 The candidate shall explain or interpret the effect of rate of absorbtion on maximum plasma concentra
tions and times of maximum plasma concentrations after drug administration.
2.04.00 The candidate shall identify, interpret, or evaluate sources of information for clarifying or answering
questions related to prescriptions, medication orders, or health care.
2.04.01 The candidate shall select appropriate books or references containing needed information (e.g.,
bioequivalence, incompatibility, drugs for emergency situations, physicochemical stability).
2.04.02 The candidate shall evaluate the suitability, accuracy, or reliability of information (e.g., pharmacokinetic
characteristics untoward effects, therapeutic efficacy) from literature sources.
4.01.02 The candidate shall identify, collect, or evaluate patient information that relates to the effectiveness of
drug therapy (e.g., clinical observations, pharmacokinetic data, laboratory test results, sensitivities).
5.01.00 The candidate shall counsel a patient or health professional regarding the indications, benefits, admin
istration, storage, or untoward effects of prescription medications.
5.01.01 The candidate shall explain the proper procedure for taking or administering the drug (e.g., dosage,
time of day, method or time of administration  before or after meals, duration of use), or for providing auxiliary
instructions about the medication.
5.01.03 The candidate shall explain cautions regarding food, drugs, chemicals, or nutrients that should be
avoided while particular medications are taken.
5.05.00 The candidate shall advise consumers regarding the selection, proper use, effects, precautions, or
contraindications of OTC products.
5.05.03 The candidate shall explain how a drug is to be taken (e.g., dosage, time of day, frequency, before or
after meals).
DL loading dose
ss
(Cp ) “average” steadystate concentration of drug in plasma during a dosing
avg
interval
ss
(Cp ) maximum concentration of drug in plasma
max
ss
(Cp ) minimum concentration of drug in plasma
min
t0 lag time
Cl cr creatinine clearance
dX
 instantaneous rate of change of amount of unchanged drug (*)
dt
X
 measured rate of change of amount of unchanged drug (*)
t
AUC area under the plasma concentrationtime curve (units: time * mass/vol
ume)
AUMC area under the first moment of the plasma concentrationtime curve (units:
2
time ⋅ mass ⁄ volume )
R accumulation factor
b intercept
f ss fraction of steadystate
n number of doses
s Laplace operator
1.10.9 SUBSCRIPTS
0 at time zero
∞ at time infinity
ss during steadystate
t at time t
T at time T
n following dose n
int intrinsic
1.10.10 SUPERSCRIPTS
x extrapolated
given that 100% bioavailability of a single I.V. bolus dose is equal to 1, and both
doses contain an equal mass of active drug.
For the struggling pharmacokinetics student, we would like to show the veracity of
this statement. Of course, it is obvious that; the reverse of the transpose is equal to
the transpose of the inverse in matrix theory. i.e.:
1 –1 –1 1
[x ] = [x ] (EQ 42)
0! = 1 (EQ 43)
Consequently,
1 –1 –1 1
([x ] – [ x ] )! = 1 (EQ 44)
By definition,
1 δ
e = 1 + 
δ
(EQ 46)
and
2
1 = cosh p 1 – ( tanh p ) (EQ 47)
Thus:
∞
1
∑ 
2 2
ln e + ( sin q ) + ( cos q ) =  (EQ 48)
n
n=0
2
Also,
∞
1
2 = ∑ 
2

n
(EQ 49)
n=0
and
1 = ln e (EQ 410)
and
2 2
1 = ( sin q ) + ( cos q ) (EQ 411)
under the stated conditions, two I.V. bolus doses given simultaneously will have
twice as much available drug as a single I.V. bolus dose.
You will agree, however, equation 11 is obvious and therefore is more easily
understood by a pharmacokineticist!
1. MicroMath Scientific Software, Inc., P.O. Box 21550, Salt Lake City, UT 841210550,
Any number multiplied by zero equals zero. Any number multiplied by infinity
( ∞ ) equals infinity. Any number divided by zero is mathematically undefined.
Any number divided by infinity is mathematically undefined.
Large or small numbers can be expressed in a more compact way using indices.
5
How Does Scientific Examples: 316000 becomes 3.16 × 10
Notation Work?
–3
0.00708 becomes 7.08 ×10
n
A × 10
The value of the integer n is the number of places that the decimal point must be
moved to place it immediately to the right of the first nonzero digit. If the decimal
point has to be moved to its left then n is a positive integer; if to its right, n is a
negative integer.
A shorthand notation (AEn) may be used, especially in scientific papers. This may
n
be interpreted as A × 10 , as in the following example:
4
2.28E4 = 2.28 ×10 = 22800
Number of
Significant Significant
Value Figures Figures
(a) 572 2,5,7 3
(b) 37.10 0,1,3,7 4
(c) 10.65 x 104 0,1,6,5 4
(d) 0.693 3,6,9 3
(e) 0.0025 2,5 2
How do I determine the Examples (c) to (e) illustrate the exceptions to the above general rule. The value 10
number of significant raised to any power, as in example (c), does not contain any significant figures;
figures? hence in the example the four significant figures arise only from the 10.65. If one
or more zeros immediately follow a decimal point, as in example (e), these zeros
simply serve to locate the decimal point and are therefore not significant figures.
The use of a single zero preceding the decimal point, as in examples (d) and (e), is
a commendable practice which also serves to locate the decimal point; this zero is
therefore not a significant figure.
What do significant fig Significant figures are used to indicate the precision of a value. For instance, a
ures mean? value recorded to three significant figures (e.g., 0.0602) implies that one can reli
ably predict the value to 1 part in 999. This means that values of 0.0601, 0.0602,
and 0.0603 are measurably different. If these three values cannot be distinguished,
they should all be recorded to only two significant figures (0.060), a precision of 1
part in 99.
After performing calculations, always “round off” your result to the number of sig
nificant figures that fairly represent its precision. Stating the result to more signifi
cant figures than you can justify is misleading, at the very least!
(a) Multiplication
A n n+m
=  × B
n m n+m n m
A ×A = A A ×B
B
(b) Division
n n n n–m
A
 = A
n–m A
 = A × B
m m B
A B
n m nm
(A ) = A
–n 1 –n
A = n As n tends to infinity ( n → ∞ ) then A → 0 .
A
1

n n
A = A
0
A = 1
2.2.5 LOGARITHMS
What is a logarithm? Some bodily processes, such as the glomerular filtration of drugs by the kidney,
are logarithmic in nature. Logarithms are simply a way of succinctly expressing a
number in scientific notation.
n
A = 10 then log ( A ) = n
where ‘log’ signifies a logarithm to the base 10, and n is the value of the logarithm
of (A).
5
Example: 713000 becomes 7.13 × 10 ,
∞
1 Where x is an inte
e = 2.7182818 ... Strictly speaking, e = 1 + ∑ x!
x=1
ger ranging from 1 to infinity ( ∞ ) ,
n
In general terms, if a number (A) is given by A = e , then by definition,
ln ( A ) = n
Where, ‘ln’ signifies the natural logarithm to the base e , and n is the value of the
natural logarithm of A .
log ( A ) = 0.4343 × ln ( A )
Because logarithms are, in reality, indices of either 10 or e , their use and manipu
lation follow the rules of indices (See Section 2.2.4).
(a) Multiplication:
n m n m n+m
To multiply N × M , where N = e and M = e ; NM = e × e = e .
By definition, ln ( NM ) = n + m ; but
n = ln ( N ) and m = ln ( M ) , hence ln ( NM ) = ln ( N ) + ln ( M )
Thus, to multiply two numbers (N and M) we take the natural logarithms of each,
add them together, and then take the antilogarithm (the exponent, in this case) of
the sum.
(b) Division
ln  = ln ( N ) – ln ( M )
N
M
m
ln ( N ) = m × ln ( N )
) = – m × ln ( N ) = m × ln 
–m 1
ln ( N
N
–m
As m tends to infinity ( m → ∞ ) , then ln ( N ) → –∞
1

m

1
ln ( m N ) = ln N =  × ln ( N )
m
ln ( 1 ) = log ( 1 ) = 0
–3
7.13 ×10 , or
0.85 –3
10 × 10 , or
– 2.15
10 .
Hence, log ( 0.00713 ) = – 2.15 , which is the result generated by most calculators.
The 3 prior to the decimal point is known as the characteristic of the logarithm; it
can be negative (as in this case) or positive, but is never found in logarithmic
tables. The .85 following the decimal point is known as the mantissa of the loga
rithm; it is always positive, and is found in logarithmic tables.
In fact 3 is a symbolic way of writing minus 3 (3) for the characteristic. In every
case the algebraic sum of the characteristic and the mantissa gives the correct
value for the logarithm.
The reason for this symbolism is that only positive mantissa can be read from anti
logarithmic tables, and hence a positive mantissa must be the end result of any log
arithmic manipulations. Note that while there are negative logarithms (when N <
1), they do not indicate that number itself is negative; the sign of a number (e.g., 
N) is determined only by inspection following the taking of antilogarithms.
Note that in both examples the value of the characteristic is the integer power to
which 10 is raised when the number is written in scientific notation.
How do I multiply using (c) Multiply 62.54 by 0.00329
logarithms?
log (62.54) = 1.7972
0.6866=1.3134
(d) We wish to find antilog (1.3134) Look up the antilog for the 0.3134 (man
tissa) in a table: it is 2058.
–1
Antilog (1.3134) = 2.058 ×10
2.2.9 DIMENSIONS
What is a unit? There are three fundamental dimensions which are used in various combinations to
express the properties of matter. Each of these dimensions has been assigned a def
inite basic unit, which acts as a reference standard.
Dimensional
Dimension Symbol Unit Unit Symbol
Length L meter m
Mass M gram g
Time T second sec
How are units made big In the metric system, which emerged from the French Revolution around 1799,
ger and smaller? there are various prefixes which precede the basic units and any derived units. The
prefixes indicate the factor by which the unit is multiplied. When the index of the
factor is positive the prefixes are Greek and have hard, consonant sounds. In con
trast, when the index is negative, the prefixes are Latin and have soft, liquid
sounds. (see Table 23).
How big is big? Examples: An average adult male patient is assumed to have a mass of 70 kilo
grams (70 kg). An average adult male patient is assumed to have a height of 180
centimeters (180 cm). A newly minted nickel has a mass of 5.000 g. Doses of
drugs are in the mg (103 g) range (occasionally g) never Kg (103 g) or larger. Stu
dents have told me that the dose that they have calculated for their patient is 108 g
(converting to common system  ~ 100 tons). I doubt it. Get familiar with this sys
tem. Note that the plural of Kg or cm is Kg or cm; do not add an “s”. In pharmacy
there are two derived units which are commonly used, even though they are
related to basic units. The Liter (L) is the volume measurement and is a cube 10
cm on a side (1L = (10cm)3 = 1000 cm3 ) while the concentration measurement
and has the units of Mass per Volume.
Why should I use units? Whenever the magnitude of a measured property is stated, it is imperative to state
the units of the measurement. Numbers are useless by themselves.
Example: The procainamide concentration range is 48 µ g/ml; stating the range
without units may lead to a potentially lethal error in which procainamide is
administered in a sufficient dose to attain a range of 48 mg/ml, which is 1000
times too large and would give rise to cardiac arrest.
mega M 6 nano n –9
10 10
kilo k 3 pico p –12
10 10
hecto h 2 femto f –15
10 10
deca da 1 atto a –18
10 10
TABLE 24
Dimensional Unit
Dimension Symbol Unit Symbol
Volume V liter l
Concentration C grams/liter g/l
Consider the following equation which defines the average concentration of a drug
FD
in blood after many repeated doses, ( C b )∞ = 
VKτ
Where:
• F is the fraction of the administered dose ultimately absorbed (Dimensions: none),
• D is the mass of the repeated dose (Dimension: M),
• V is the apparent volume of distribution of the drug (Dimension: V = L )
–1
• K is the apparent firstorder rate constant for drug elimination (Dimension: T ),
Writing the dimensions relating to the properties of the righthand side of the equa
tion gives:
M  M
 = 
–1 V
V⋅T ⋅T
M
Thus ( C b )∞ has the dimensions of  , which are correctly those of concentration.
V
2.3 Calculus
What is Calculus? Calculus concerns either the rate of change of one property with another (differen
tial calculus), such as the rate of change of drug concentrations in the blood with
time since administration, or the summation of infinitesimally small changes (inte
gral calculus), such as the summation of changing drug concentrations to yield an
assessment of bioavailability. In this discussion a few general concepts will be pro
vided, and it is suggested an understanding of graphical methods should precede
this discussion.
3
Consider the following relationship: y = x
As can be seen from the graph (Figure 21), a nonlinear plot is produced, as
expected.
70
60
50
40
30
20
10
0
1 2 3 4
(Question: How could the above data be modified to give a linear graph?)
y2 – y1 ∆y
 = 
x2 – x1 ∆x
But, as can be seen (Figure 1), the slope is not constant over the range of the graph;
it increases as x increases. The slope is a measure of the change in y for a given
change in x. It may then be stated that:
“the rate of change of y with respect to x varies with the value of x.”
3
We need to find the value of the slope of the line y = x when x = 2 (See Figure
1). Hence, we may choose incremental changes in x which are located around
x ≈ 2.
∆y

x1 x2 ∆x y1 y2 ∆y ∆x
0 4 4 0 64 64 16.000
1 3 2 1 27 26 13.000
1.5 2.5 1.0 3.375 15.625 12.250 12.250
1.8 2.2 0.4 5.832 10.648 4.816 12.040
1.9 2.1 0.2 6.859 9.261 2.042 12.010
1.95 2.05 0.1 7.415 8.615 1.200 12.003
As may be seen, the value of the slope ∆y tends towards a value of 12.000 as the
∆x
magnitude of the incremental change in x becomes smaller around the chosen
value of 2.0. Were the chosen incremental changes in x infinitesimally small, the
true value of the slope (i.e., 12.000) would have appeared in the final column of
the above table.
Calculus deals with infinitesimally small changes. When the value of ∆x is infini
tesimally small it is written dx and is known as the derivative of x. Hence,
dy
 = f ( x )
dx
Where dy/dx is the derivative of y with respect to x and f ( x ) indicates some func
tion of x.
3
y = x
Hence,
3
y + dy = ( x + dx ) (EQ 213)
Multiplying out:
3 2 2 3
y + dy = x + 3x ( dx ) + 3x ( dx ) + ( dx ) (EQ 214)
(c) The change in y is obtained by subtraction of the original expression from the
last expression. (i.e., Eq. 2  Eq. 1)
2 2 3
dy = 3x ( dx ) + 3x ( dx ) + ( dx ) (EQ 215)
dy
 = 3x 2 + 3x ( dx ) + ( dx )2
dx
dy
 = 3x 2 (EQ 216)
dx
2
Hence the derivative of y with respect to x at any value of x is given by 3x .
(d) In section 2.3.4 we saw how the true value of the slope (i.e., dy/dx) would be
12.0 when x = 2 . This is confirmed by substituting in Equation 116.
dy
 = 3x 2 = 3 ( 2 2 ) = 12
dx
Although the rate of change of one value with respect to another may be calculated
as above, there is a general rule for obtaining a derivative.
n
If y = Ax
then
dy
 = nAx n – 1
dx
The Rules of Indices may need to be used to obtain expressions in the form
n
y = Ax
(e.g., if y = 5 x)
0
(a) If y = Ax ,
dy
Hence,  = 0
dx
dy 1
then  =  .
dx x
Ax
(c) Accept that if y = Be where B and A are constants, and e is the natural
dy Ax
base then  = ABe
dx
This derivative will be useful in pharmacokinetics for finding the maximum and
minimum concentrations of drug in the blood following oral dosing.
n
(a) If y = Ax , then
dy n–1
 = nAx
dx
n
(b) If y = Ax + A ,
dy n–1 n–1
then  = nAx + 0 = nAx
dx
Both of the original expressions, although different, have the same derivative. This
fact is recognized later when dealing with integral calculus.
Thus,
dy
 = Ax n , or
dx
n
dy = Ax ⋅ dx
To integrate,
∫ dy ∫ Ax dx = A ∫ x dx
n n
y = =
n+1
Ax
A ∫ x dx =  + A
n
n+1
Where A is the constant of integration However, there is one exception  the rule
is not applicable if n = – 1
dy 2
Example: If  = 3x (See section 2.3.5),
dx
2+1
3x
then y =  + A , and
2+1
3
y = x +A
There has to be a constant in the final integrated expression because of the seeming
3 3
anomaly referred to in section 2.3.8. As mentioned, both y = x and y = x + A
dy 2
will give, on differentiation,  = 3x .
dx
So whether or not a constant is present and, if so, what is its value, can only be
decided by other knowledge of the expression. Normally this other knowledge
takes the form of knowing the value of y when x = 0 .
In the case of our graphical example we know that when x = 0 , then y = 0 . The
integrated expression for this particular case is:
3
y = x + A , therefore
3
0 = 0 + A , thus A = 0
In some examples, such as firstorder reaction rate kinetics, the value of A is not
zero.
It occurs when n = – 1
1
y = A ∫ x dx = A ∫  dx
–1
x
Upon integration, y = A ⋅ ln ( x ) + A
dy
 = Be Ax
dx
then,
Ax
Be
y =  + A
A
This integral will be useful for equations which define the bioavailability of a drug
product.
(a) Consider,
2
c = 3t ( t – 2 ) + 5
3 2
c = 3t – 6t + 5
dc
 = 9t 2 – 12t
dt
dc 2
(b) Consider,  = 3t ( t – 4 ) = 9t – 12t
dt
Then rearranging,
2
dc = 9t ⋅ dt – 12 ⋅ dt
∫ dc
3 2
c = = 3t + A – 6t + B
3 2
c = 3t = 6t + D
where D = A + B
2 2
c = 3t + 6t + 5
– dC p
 = KC p
dt
Rearranging,
1
– K ⋅ dt =  ⋅ dC p
Cp
1
– Kt = – K ∫ dt = ∫ 
 ⋅ dC p
Cp
– Kt = ln ( C p ) + A
Substituting, 0 = ln ( C p )0 + A
Or,
A = – ln ( C p )0
Hence
– Kt = ln ( C p ) – ln ( C p ) 0
or,
ln ( C p ) = ln ( C p ) 0 – Kt
or,
– Kt
Cp = ( C p )0 ⋅ e
2.4 Graphs
Why do we graph? We would like to organize the chaotic world around us so that we can predict (see
into the future) and retrodict (see into the past) what will happen or has happened.
Our recorded observations are collectively known as data. We make a theory
about what we think is happening and that theory is expressed in an equation. That
determines our paradigm of how we see the world. This paradigm is expressed as
a graph. The language of science is mathematics and graphs are its pictures.
TABLE 26
English Science
Observations Data
Theory Equations
Paradigms (pictures) Graphs
What is a graph? A graph is simply a visual representation showing how one variable changes with
alteration of another variable. The simplest way to represent this relationship
between variables is to draw a picture. This pictorializing also is the simplest way
for the human mind to correlate, remember, interpolate and extrapolate perfect
data. An additional advantage is it enables the experimenter to average out small
deviations in experimental results (nonperfect, real data) from perfect data. For
example:
Perfect Real
3 5 4.6
2 3 3.4
1 1 0.6
0 +1 +0.8
+1 +3 +3.4
+2 +5 +4.4
2
4
6
3 2 1 0 1 2
Simply looking at the columns x and y (real) it might be difficult to see the rela
tionship between the two variables. But looking at the graph, the relationship
becomes apparent. Thus, the graph is a great aid to clear thinking. For every graph
relating variables, there is an equation and, conversely for every equation there is a
graph. The plotting of graphs is comparatively simple. The reverse process of find
ing an equation to fit a graph drawn from experimental data is more difficult,
except in the case of straight lines.
The ‘y’ variable, known as the dependent variable, is depicted on the vertical axis
(ordinate); and the ‘x’ variable, known as the independent variable, is depicted on
the horizontal axis (abscissa). It is said that ‘y’ varies with respect to ‘x’ and not
‘x’ varies with ‘y’.
A decision as to which of the two related variables is dependent can only be made
be considering the nature of the experiment. To illustrate, the plasma concentration
of a drug given by IV bolus depends on time. Time does not depend on the plasma
concentration. Consequently, plasma concentration would be depicted on the ‘y’
axis and time on the ‘x’ axis.
Any point in the defined space of the graph has a unique set of coordinates: 1) the
‘x’ value which is the distance along the ‘x’ axis out from the ‘y’ axis and always
comes first; and 2) the ‘y’ value which is the distance, along the ‘y’ axis up or
down from the ‘x’ axis, and always comes second. Several points are shown in
Figure 2. For example, (0,1) is on the line and (1,0) is not.
The intersection of x and y axis is the origin with the coordinates of (0,0). In two
dimensional spaces, the graph is divided into 4 quadrants from (0,0), numbered
with Roman numerals from I through IV. It should be readily apparent that the
coordinates for all points within a particular quadrant are of the same sign type i.e.,
y = mx + b
Where:
• y = dependent variable
• x = independent variable
• m = slope of the straight line = ∆
y
∆x
• b = the y intercept (when x = 0)
• or if the equation can be “linearized”, e.g.,
mx′
y′ = b′e is not linear. However. ln y′ = ln b′ + mx′
– Kt
C p = C p0 e
y = b + mx
The graphs that yield a straight line are the ones with the ordinate being ln C p0 ,
and the abscissa being t .
• C p versus t
• C p versus ln t
• ln C p versus ln t
The appropriate use of a natural logarithm in this case serves to produce linearity.
However, the use of logarithms does not automatically straighten a curved line in
all examples. Some relationships between two variables can never be resolved into
( n – m) (n – m + 1) x
a single straight line, e.g., y = k 0 + k 1 x + k2 x + … + ( k n )x
where n ≥ 2 ;n = m + 1 or
K a FD Kt –K t
C p =  ⋅ ( e – e a )
V ( Ka – K )
(It is possible to resolve this equation into the summation of two linear graphs
which will be shown subsequently.)
µg
C p 
t (min) mL ln C p
12 3.75 1.322
40 2.80 1.030
65 2.12 0.751
90 1.55 0.438
125 1.23 0.207
173 0.72 0.329
The differences in both the yvalues and the xvalues may be measured graphically
to obtain the value of the slope, m. Then knowing the value of m, the value of K
may be found.
101
g/mL)
u
Caffeine Concentration (
100
101
0 50 100 150 200
Time (min)
y = m⋅x+b
• y is the dependent variable
• x is the independent variable
• m is the slope of the line
• b is the intercept of the line
The equation for the slope of the line using linear regression is:
( Σ ( x ) ⋅ Σ ( y ) ) – ( n ⋅ Σ ( x ⋅ y ) )
m = 
2 2
[ Σ ( x ) ] – ( n ⋅ Σ( x ) )
2
X Y X X⋅Y
12 1.322 144 15.864
40 1.030 1600 41.2
65 0.751 4225 48.815
90 0.438 8100 39.42
125 0.207 15625 25.875
173 0.329 29929 56.917
ΣX = 505 ΣY = 3.239 2
ΣX = 59623 ΣXY = 114.257
2
( ΣX ) = 255025
Σx Σy
x =  = 4.167 y =  = 0.5398
n n
Using the data from table 210 in the equation for the slope of the line
( 505 ⋅ 3.239 ) – ( 6 ⋅ 114.257 ) ·
m =  = – 0.01014
255025 – ( 6 ⋅ 59623 )
It is important to realize that you may not simply take any two data pairs in the
data set to get the slope. In the above data, if we simply took two successive data
pairs from the six data pairs in the set, this would result in five different slopes
( ∆x ⁄ ∆y ) ranging from 0.0066 to 0.0125 as shown in table 211. Clearly, this is
unacceptable. Even to guess, you must plot the data, eyeball the best fit line by
placing your clear straight edge through the points so that it is as close to the data
as possible and look to make sure that there are an equal number of points above
the line as below. Then take the data pairs from the line, not the data set.
∆y

Time (x) ln Conc. (y) ∆x ∆y ∆x
12 1.322 28 0.292 0.0104
40 1.030 25 0.28 0.0112
65 0.751 25 0.312 0.0125
90 0.438 35 0.231 0.0066
125 0.207 48 0.536 0.0112
173 0.329
(a) Not knowing the value of m; The graph may be extrapolated, or calcu
lations performed, at the situation where t = 0 . In this case b = ln C p0 .
• Secondly, the graph may be extrapolated or calculations performed, at the situation where
t = 0 . In this case, b = ln C p
If the size of the graph does not permit physical extrapolation to the desired value,
the required result may be obtained by calculation. The values of m and b must be
found as shown above. Then: y' = mx' + b , where x' is the selected value of x,
and y' is the new calculated value for y.
The more closely the experimental points fit the best line, and the higher the num
ber of points, the more significant is the relationship between y and x. As you may
expect, statistical parameters may be calculated to indicate the significance.
What good is a straight By using all the experimental data points, calculations may be made to find the
line? optimum values of the slope m, and the intercept, b. From these values the corre
lation coefficient (r).and the tvalue may be obtained to indicate the significance.
Exact details of the theory are available in any statistical book, and the calculations
may most easily be performed by a computer using The Scientist or PKAnalyst in
this course.
The advantage of computer calculation is that it gives the one and only best fit to
the points, and eliminates subjective fitting of a line to the data.
In mathematical studies, the scales of the x and y are almost always equal but very
often in plotting chemical relations the two factors are so very different in magni
tude that this can not be done. Consequently, it must be borne in mind that the rela
tionship between the variables is given by the scales assigned to the abscissa and
ordinate rather than the number of squares counted out from the origin.
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0 2 4 6 8 10
10
8
6
4
2
0
0 2 4 6 8 10
For example (shown in Figure 25), these two parabolic curves represent the same
equation the only difference is the scales are different along the y axis.
Frequently it is not convenient to have the origin of the graph coincide with the
lower left hand corner of the coordinate paper. Full utilization of the paper with
suitable intervals is the one criteria for deciding how to plot a curve from the
experimental data. For example, the curve below (Figure 26) is poorly planned,
where the following (Figure 27) is a better way of representing the gas law
PV = nRT
50
40
30
20
10
0
0 4 8 12 16 20
25
20
15
10
5
0
1 2 3 4 5 6 7 8 9 10
P ( )
2
Previously variables were raised to constant powers; as y = x . In this section
x
constants are raised to variable powers; as y = 2 . Equations of this kind in which
the exponent is a variable are called (naturally) exponential equations. The most
x
important exponential equation is where e is plotted against x .
ng
Concentration 
Time (hours) ml
0.25 1900
.75 1500
1.5 1300
4 900
6 600
8 390
These can be illustrated in three different ways (Figures 28, 29, 210),
• Concentration vs. time directly
• Log concentration vs. time directly
• Log concentration vs. time with concentration plotted directly on to log scale of ordinate.
2000
1800
1600
1400
1200
1000
800
600
400
200
0 1 2 3 4 5 6 7 8
3.200
Log Concentration  Time Curve
3.100
3.000
2.900
2.800
2.700
2.600
2.500
2.400
2.300
0 1 2 3 4 5 6 7 8
10000
1000
100
0 1 2 3 4 5 6 7 8
Graphing is much easier because the graph paper itself takes the place of a loga
rithmic table, as shown in Figure 110.
Only the mantissa is designated by the graph paper. Scaling of the ordinate for the
characteristic is necessary. The general equation y = Be ax can be expressed as a
straight line by basic laws of indices.
ax
ln y = ln B + ln ( e ) → ln y = ln B + ax or ln y = ax + ln B
One axis is printed with logarithmic spacing, and the other with arithmetic spac
ing. It is used when a graph must be plotted as in the example (Figure 14)
y = log [ C p ] and x = t .
b) obtaining the value of the slope is difficult. In this instance the slope is given by:
y2 – y1 ln [ C p ] 2 – ln [ C p ] 1
m = 
 = 
x2 – x1 t2 – t1
Hence, before calculating the value of m, the two selected values of [ Cp ] 1 and [ Cp ] 2
must be converted, using a calculator, to ln [ Cp ] 1 and ln [ C p ] 2 in order to satisfy the
equation. The same problem may arise in obtaining the intercept value, b.
The two problems may be avoided by plotting the same data on ordinary paper, in
which case the vertical axis is labelled “log plasma concentration”. However, in
this instance the ordinary values of [ C p ] must be converted to ln [ Cp ] prior to plot
ting. It is the ln [ Cp ] values which are then plotted.
The calculation of the slope is direct in this case, as the values of y 1 and y 2 may be
read from the graph. Hence, one must consider the relative merits of semilogarith
mic and ordinary paper before deciding which to use when a log plot is called for.
In the case of semilog graphs the slope may be found in a slightly different manner,
i.e., taking any convenient point on the line ( y 1 ) we usually take the as the second
point, ( y 2) one half of ( y 1 ) . Thus,
y1
ln  ln 
 1
ln y 1 – ln ( ( 1 ⁄ 2 )y 1 ) ( 1 ⁄ 2 )y 1 1⁄2 ln 2  0.693
m = 
 = 
 =  =  = 
t 1 – t2 t 1 – t2 t 1 – t2 t1 – t2 –t1 ⁄ 2
(in which case, t 2 – t 1 is called the halflife t½ ). Since t1 < t2 , then t1 – t2 = –t1 ⁄ 2
0.693 0.693
because m =  = – k
–t1 ⁄ 2
and k =  .
t1 ⁄ 2
a
Functions of the type y = Bx give straight lines when plotted with logarithms
along both axis.
The utility of these procedures requires proper graphing techniques. The picture
that we draw can cause formation of conceptualizations and correlations of the
data that are inconsistent with the real world based simply on a bad picture. Conse
quently the picture must be properly executed.
The most common error is improper axes labelling. On a single axis of rectilinear
coordinate paper (standard graph paper), a similar distance between two points
corresponds to a similar difference between 2 numbers. Thus,
40
30
20
10
0
0 5 10 15 20 25 30
40
30
20
10
1
0
0 2 5 10 20 30
Obviously, the distance (Time) on the graph 12 between 0 and 2 hours should not
be the same as the distance between 10 and 20 hours. It is, and therefore Figure 2
12 is wrong.
Similarly, the use of similar paper may result in some confusion. With logarithms
the mantissa for any string of numbers, differing only by decimal point placement,
is the same. What differentiates one number from another, in this case, is the char
acteristic. Thus,
Logarithmic Plot
103
234
102
23.4
101
Y axis (units)
2.34
100
0.234
101
1.0 1.5 2.0 2.5 3.0 3.5 4.0
X axis (units)
Thus, we see, in Figure 213, the cycle on the semilog paper to relate to orders of
magnitude (e.g., 1, 10, 100, 1000, etc.) and consequently the characteristic of the
exponent.
The third common problem is labelling the log axis as log “y”. This is improper. It
is obvious from the spacing on the paper that this function is logarithmic, and thus
the axis is simply labelled “y”.
There are almost as many different errors as there are students and it is impossible
to list them all. These few examples should alert you to possible problems.
0 1 2 3 4 5
Find the slope by taking any two values on the Y axis such that the smaller value is
one half of the larger. The time that it takes to go from the larger to the smaller is
the halflife. Dividing 0.693 by the halflife yields the rate constant.
0 2 4 6 8 10 12
FIGURE 216. Curved line which goes up and then straight down on semilog paper.
0 5 10 15 20 25
Find the terminal slope by taking any two values on the Y axis such that the
smaller value is one half of the larger. The time that it takes to go from the larger to
the smaller is the halflife. Dividing 0.693 by the halflife yields the rate constant.
Plot type one is reasonably easily evaluated. There are 2 important things that can
be obtained: Slope and Intercept. However, the slope and intercept have different
meanings dependent on the data set type plotted. The slope is the summation of all
the ways that the drug is eliminated, K.
Plot type two is not usually evaluated in its present form as only the plateau value
can be obtained easily. But again it has different meanings dependent on the data
plotted.
Usually urine data of this type (parent compound  IV bolus) is replotted and eval
uated as plot 1 (above). Infusion data can be replotted using the same techniques,
but usually is not.
Plot type 3 must be stripped of the second rate constant from the early time points,
thus:
There are 3 things that can be obtained from the plot: the terminal slope (the
smaller rate constant), the slope of the stripped line (the larger rate constant) and
the intercept. The rate constants obtained from a caternary chain (drug moving
from one box to another in sequence in compartmental modeling) are the summa
tion of all the ways that the drug is eliminated from the previous compartment and
all the ways the drug is eliminated from the compartment under consideration. See
LaPlace Transforms for further discussion.
Again, dependent on the data set type being plotted they will have different values.
Data
Type Y axis X axis S1 S2 Intercept
IV Bolus Metabolite conc. Time K small Klarge km ⋅ X 0
Parent 
( K l arg e – K smal l ) ⋅ V dm
IV Bolus dXmu
 excretion
Time K small Klarge k mu ⋅ k m ⋅ X 0
Parent dt (mid) 

K l arg e – K smal l
rate of metabolite
into urine
Oral Drug conc. Time K small Klarge k a ⋅ fX 0


( K l arg e – K smal l ) ⋅ V d
Models are simply mathematical constructs (pictures) which seem to explain the
relationship of concentration with time (equations) when drugs are given to a per
son (or an animal). These models are useful to predict the time course of drugs in
the body and to allow us to maintain drug concentration in the therapeutic range
(optimize therapy). The simplest model is the one used to explain the observations.
We model to summarize data, to predict what would happen to the patient given a
dosage regimen, to conceptualize what might be happening in disease states and to
compare products. In every case, the observations come first and the explanation
next. Given that a data set fits a model, the model can be used to answer several
different types of questions about the drug and how the patient handles the drug
(its disposition), for example: if the drug were to be given by an oral dose, how
much is absorbed and how fast? Are there things which might affect the absorp
tion, such as food or excipients in the dosage form itself. What would happen if the
drug were to be given on a multiple dose regimen? What if we increased the dose?
etc.
Again, the rate constant, k , tells the magnitude of the rate, k⋅X.
k12 k23
X1 X2 X3
The building blocks are k 12 ⋅ X1 and k 23 ⋅ X2 . Every arrow that touches the compart
ment of interest becomes part of the differential equation. If the arrow goes to the
box, it’s positive; if it goes away from the box, it’s negative.
To find dX1 ⁄ dt (the rate of change of X 1 with time), we simply add up all of the
rates which affect X1 (all of the arrows that touch X1 )
dX 1
 = – k 12 ⋅ X 1
dt
and thus:
dX 2
 = k 12 ⋅ X 1 – k 23 ⋅ X2
dt
dX 3
 = k 23 ⋅ X 2
dt
(Note: the first subscript of the rate constant and the subscript of the box from
which it originates are the same.)
You should be able to integrate any differential equation developed from any
model (within reason) that we can conceptualize.
(Note: Each subsequent variable is dependent on the ones that precedes it. In fact,
the solutions to the preceding variables are substituted into the differential to
remove all but one of the time dependent functions  the one that we are currently
attempting to solve.)
A simplified picture (mathematical construct) of the way the body handles drug is
one where the body can be conceived to be a rapidly stirred beaker of water (a sin
gle compartment). We put the drug in and the rate at which the drug goes away is
proportional to how much is present (first order). Thus the assumptions are:
• Body homogeneous (one compartment)
• Distribution instantaneous
• Concentration proportional to dose (linear)
• Rate of elimination proportional to how much is there. (First order)
It is important to note that we know some of these assumptions are not true. It is of
little consequence, as the data acts as if these were true for many drugs. The visual
image which is useful is one of a single box and a single arrow going out of the
box depicting one compartment with linear kinetics. The dose is placed in the box
and is eliminated by first order processes. In many cases, more complicated mod
els (more boxes) are necessary to mathematically mimic the observed plasma ver
sus time profile when one or more of these assumptions are not accurate. For
example, the two compartment (or multicompartment) model results when the
body is assumed to not be homogeneous and distribution is not instantaneous.
Basically, the LaPlace Transform is used to solve (integrate) ordinary, linear differ
ential equations. In pharmacokinetics such equations are zero and firstorder rate
equations in which the independent variable is time. For instance, if a differential
equation describing the rate of change of the mass of drug in the body with time is
integrated, the final equation will describe the mass of drug actually in the body at
any time.
2.6.2 SYMBOLISM
“a bar will be placed over the dependent variable which is being transformed”.
Example:
If X is the mass of unchanged drug in the body at any time, then X is the LaPlace
Transform of this mass.
When drugs enter the body, they will encounter many different fates. It is impor
tant to set up the possible fates of the drug by creating a well thought out flow
chart or scheme in order to follow all the events that are occurring in the body as
described by the pharmacokinetic description of the drug. For example, a drug
may be excreted unchanged or may undergo hepatic metabolism to yield active or
inactive metabolites. All of these components are part of pharmacokinetics, which
by definition, includes ADME (the Absorption, Distribution, Metabolism and
Excretion of drugs), and must be considered. This flow chart becomes the back
bone or the framework upon which to build the equations which describe the phar
macokinetics of the drug. The differential equations result as a direct consequence
of the flow chart. Using Laplace transforms, the integration of these differential
equations are simplified and provide the pharmacokineticist to (easily?) keep track
of all of the variables in the equation. If the drug scheme or flow chart is set up
incorrectly, this would have a definite negative impact or the expected equations
(as well as the answers and your grade). Below are two examples of how to con
struct a flow chart. Note that not all drugs follow the same flow chart and it is
quite possible that you will need only to use a portion of these examples when con
struction your own.
Dose
Parent Compound kf ku
Xf X Xu
km
kmf kmu
Metabolite Xmf Xm Xmu
Using the pharmacokinetic symbolism from chapter one, the compartments are
named and placed: metabolites below (or above the plane of the parent com
pound): compounds going into the urine, to the right; and compounds going into
the feces, to the left of the compounds in the body. The rate constants connecting
the compartments also follow the symbolism from chapter one. In the above flow
chart, K, the summation of all the ways that X is removed from the body, is ku + kf
+ km while K1, the summation of all the ways that Xm is removed from the body,
is kmu +kmf.
Only those compartments are used which correspond to the drug’s pharmacoki
netic description, thus when a drug is given by IV bolus and is 100% metabolized
with the metabolite being 100% excreted into the urine the model would look like
this:
Dose
km
kmu
Xm Xmu
Thus in this flow chart, K, the summation of all the ways that X is removed from
the body, is km while K1, the summation of all the ways that Xm is removed from
the body, is kmu.
Drugs sometimes are metabolized to two (or more) different metabolites. In the
first case, the drug is metabolized by two separate pathways resulting in this flow
chart:
Dose
km1
kf X ku Xu
Xf
km2
In this flow chart, K, the summation of all the ways that X is removed from the
body, is ku + kf + km1 + km2 while K1, the summation of all the ways that Xm1 is
removed from the body, is kmu1 +kmf1 and K3, the summation of all the ways
that Xm2 is removed from the body, is kmu2 + kmf2.
While in a second case, the drug is metabolized and the metabolite is further
metabolized resulting in this flow chart:
Dose
kf X ku Xu
Xf
km1
kmf1 kmu1
Xmf1 Xm1 Xmu1
km2
In this flow chart, K, the summation of all the ways that X is removed from the
body, is ku + kf + km1 while K1, the summation of all the ways that Xm1 is
removed from the body, is kmu1 +kmf1+ km2 and K3, the summation of all the
ways that Xm2 is removed from the body is kmf2 + kmu2.
Both of these flow charts result in very different end equations, so it is imperative
that the flow charts accurately reflect the fate of the drug.
(Scheme I)
ku
X Xu
X u is the cumulative mass of unchanged drug in the urine up to any time, and k u is
the apparent firstorder rate constant for excretion of unchanged drug.
a. The building block is the arrow and what it touches. This first box (compart
ment) of interest is [ X ] . The arrow ( k u) is going out, therefore, the rate is going out
and is negative, thus
dX
 = –k u X (EQ 217)
dt
sX – X0 = – k u X (EQ 218)
Note that because the independent variable (time) did not appear on the righthand
side of equation 217, neither did the LaPlace Operator, s, appear there in equation
218. All that was necessary was to transform the dependent variable ( X ) into X .
Hence, the table was only required for transforming the lefthand side of equation
218.
sX + k u X = X0
X ( s + k u ) = X0
X0
X =  (EQ 219)
s + ku
A
LetX0 = A Letk u = a X =  (EQ 220)
(s + a)
Note that X is the only transformed dependent variable and is on the lefthand side
of equation 219.
–ku t
X = X0e (EQ 221)
A
Note that the righthand side of equation 221 was analogous to  in the
(s + a)
table, because X0 is a constant (the initial dose administered). The lefthand side
of equation 221 could be converted back without the table.
Look at Scheme I again. Consider how the drug goes from the body into the urine.
The next box of interest is Xu . The arrow is coming in, therefore the rate is com
ing in and is positive. thus,
dXu
 = k u X (EQ 222)
dt
sX u – ( X u ) 0 = k u X (EQ 223)
But, at zero time, the cumulative mass of unchanged drug in the urine was zero:
that is ( Xu ) 0 = 0 .
sX u = k u X (EQ 224)
ku X
Xu = 
 (EQ 225)
s
Note that there are two transformed dependent variables. One of them ( X ) can be
replaced by reference to equation 219.
ku X0
Xu = 
 (EQ 226)
s(s + ku)
A
Let ( k u X0 ) = A Let ( k u ) = a X =  (EQ 227)
s(s + a)
–k t
kuX0 ⋅ ( 1 – e u )
X u = 
ku
Where k u X 0 and k u are analogous to “A” and “a” respectively in the table. Sim
plifying,
– kut
Xu = X0 ( 1 – e ) (EQ 228)
During the intravenous infusion of a drug, its excretion may be represented by the
following pharmacokinetic scheme:
(Scheme II)
Infusion Q ku
X Xu
Where Q is the zeroorder infusion rate constant (the drug is entering the body at a
constant rate and the rate of change of the mass of drug in the body is governed by
the drug entering the body by infusion and the drug leaving the body by excretion).
The drug entering the body does so at a constant (zeroorder) rate.
dX
 = Q – k u X (EQ 229)
dt
Q
sX – X 0 =  – k u X
s
Note that because Q is a rate, and is therefore a function of the independent vari
able (time), its transformation yields the LaPlace Operator. In this case, Q was
analogous to “A” in the table. But, at zero time, the mass of unchanged drug in the
body was zero: that is, X0 = 0
Q
sX =  – k u X (EQ 230)
s
Q
X =  (EQ 231)
s ( s + ku )
A
Let ( Q = A ) Let ( k u = a ) X =  (EQ 232)
s( s + a)
2.6.8 CONCLUSIONS
The final integrations (Eqs. 24, 24, and 28) are not the ultimate goal of pharmaco
kinetics. From them come the concepts of:
1. (a) elimination halflife
1. (b) apparent volume of drug distribution
2. (c) plateau drug concentrations
These, and other concepts arising from still other equations, are clinically useful.
It is also possible to see certain patterns which begin to emerge from the derivation
of the equations. For example, for a drug given by IV bolus the equation is
monoexponential, with the exponent being K, summation of all the ways that the
drug is removed form the body. A graph of the data (Cp v T on semilog paper)
results in a straight line the slope of which is K, always. If the drug is entirely
metabolized K = km. If the drug is entirely excreted unchanged into the urine, K =
ku. If the drug is metabolized and excreted unchanged into the urine, K = km +ku.
thus K can have different meanings for different drugs, depending on how the
body removes the drug. Following the drug given by IV bolus a second example
of a pattern would be that of the data of the metabolite of the drug. From the
LaPlace, the equation for the plasma concentration of the metabolite of the drug
has in it K and K1, the summation of all the ways that the metabolite is removed
from the body, always. K1 would have different meanings depending on how the
metabolite is removed from the body.
After several years teaching, I was fortunate to have a resident rotate through our
pharmacokinetic site. She had come with a strong Pharmacokinetcs background
and during our initial meeting, she had told me that she had a copy of John Wag
ner’s new textbook on pharmacokinetcs. She was excited that, finally, there was a
compilation of all the equations used in pharmacokinetics in one place.
“There are over 500 equations in the new book and I know every one,” she said.
“I’m not sure which one goes with which situation, though.” OOPS!
Throughout this text and on each exam, each equation is derived from first princi
ples using scientific method, modeling and LaPlace Transforms in the hopes that
memorization will be minimized and thought (and consequently proper interpreta
tion) would be maximized.
m is a power constant
A A

s
At A

2
s
At
m A ( m! )

m+1
s
– at A
Ae 
s+a
m – at A
At e 

m+1
(s + a)
– at A
A(1 – e ) 
 s (s + a )
a
– at A 
At (1 – e )
 – A
 
2
a a
2 s (s + a)
– at As – B
– at B( 1 – e ) 
Ae –  s (s + a )
a
– at As – B 
A + B
  – Bt
1–e
 
a a a
2
s (s + a)
– bt – at A
A ( e – e ) 

 (s + a)(s + b)
(a – b)
– bt – at A
A
 1
– e  
1 – e  

(a – b) b –
a s( s + a )( s + b )
1 – e –bt 1 – e –at A
At 
A 

 –  –  2
s ( s + a) ( s + b)
ab ( a – b ) b2 a2
1 – at – bt As – B 
 [ ( B + Aa )e – ( B + Ab )e ] 
( a – b) (s + a)(s + b)
As – B 
1 ( 1 – e –bt ) ( 1 – e – at ) 
 – bt – at
A ( e – e ) – B  –  s( s + a )( s + b )
(a – b) b a
( 1 – e –bt ) ( 1 – e – at ) As – B
1 B B Bt 
( a – b ) b 
 A + 
  – A + 
 –  2
s ( s + a) ( s + b)
b a a ab
– ct – bt – at A
e e e 

A  +  +  (s + a)(s + b)(s + c)
(a – c)(b – c) (a – b )(c – b) (b – a )(c – a)
– ct – bt – at A
(1 – e ) (1 – e ) (1 – e ) 
A  +  +  s( s + a )( s + b )( s + c )
c( a – c )( b – c ) b( a – b)( c – b ) a( b – a )( c – a)
– ct – bt – at A
At (1 – e ) ( 1 – e )  
(1 – e )  

 – A  +  + 2 2
bc 2 2 s ( s + a) ( s + b ) ( s + c )
c ( a – c) ( b – c ) b ( a – b) ( c – b) a ( b – a )( c – a)
dX
 sX – X 0
dt
(m + 1 ) A
At 
 m
(m + 1) s
Dose
X ku Xu
sX – X0 = –kuX
sX + kuX = X o
X ( s + k u )= Xo
Xo
X = 
s + ku
A
Let ( X0 ) = A , k u = a ,X = 
(s + a)
– kut
X = Xo e
Dose
X ku Xu
dX
 = – k u X
dt
sX – X0 = –kuX
sX + kuX = X o
X ( s + k u )= Xo
Xo
X =  You only need to go this far because you
s + ku
need to know X to put it in the equation for Xu. Thus:
dX
u = k u X
dt
X o ku
sX u = 

(s + ku)
Xo ku
X u = 

s(s + ku)
A
Let ( X0 k u ) = A , k u = a , X u = 
s( s + a )
– kut
ku X o ( 1 – e )
X u = 

ku
km ⋅ Xo
X m = 

( s + k mu ) ( s + k m )
Dose Let ( k m X 0 ) = A , k m = a = K , k mu = b = K1
A
X m = 
X (s + a)(s + b )
( km ⋅ X o ) –k t –k t
 ⋅ ( e mu – e m ) or
X m = 
km ( k m – k mu )
( km ⋅ Xo )
Xm kmu Xmu  ⋅ ( e – K 1t – e –K t ) in general terms.
X m = 
( K – K1 )
Xo
X = 
s + km
A
Let ( X0 ) = A , k m = a , X = 
(s + a)
– kmt
X = Xo e
dX
m = k m X – k mu X m
dt
sX m – Xm0 = k m X – kmu X m
Xm kmu Xmu
dXm
 = k m X – k mu X m
dt
sX m – Xom = k m X – kmu X m
sX m + k mu Xm = k m X
o X
substitute previously solved X = 
s + km
km Xo
X m ( s + k mu ) = 
s + km
km X o
X m = 

( s + k mu ) ( s + k m )
– kmt – kmut
km Xo ( e –e )
X m = 

( k mu – k m )
dXmu

 = k mu Xm
dt
sX mu – Xom = k muX m
Remember at time zero,
sX mu = K1X m
Dose
( k mu ) ( kmXo )
sX mu = 
( s + K1 ) ( s + K )
ku Xu
X ( k mu ) ( k m ) ( Xo )
X mu = 

s ( s + K1 ) ( s + K )
km
k mu k m X o 1 – e – Kt 1 – e – K1t
X m u =   – 
K1 – K K K1
Xm kmu Xmu
dX
 = – k u X – k m X
dt
sX – Xo = – k u X – k m X
sX + k u X + k m X = X o
X ( s + ku + km ) = Xo
( ku + km ) = K
Xo
X = 
s+K
– Kt
X = Xo e
dXm
 = k m X – k mu Xm = k m X – K1Xm
dt
sXm – X om = k m X – K1Xm
sX m + K1Xm = k m X
km Xo
X m = 
( s + K1 ) ( s + K )
Q X ku Xu
Q –k t
X =  ( 1 – e u ) or X = Q
 ( 1 – e –Kt )
ku K
Q X ku Xu
Here K = ku
dX
 = Q – k u X
dt
Q
sX – Xo =  – k u X
s
Q
sX + k u X = 
s
Q
X ⋅ ( s + k u ) = 
s
Q
X = 
s ⋅ (s + ku )
dX
u = k u X
dt
sX u – Xo = k u X
sX u = k u X
ku Q
sX u = 

s ⋅ (s + ku)
ku Q
X u = 
2

s ⋅ ( s + ku )
k u Qt 1 – e –kut
X u =  – Qk u 

ku k2 u
– kut – Kt
(1 – e ) (1 – e )
X u = Qt – Q  or Xu = Qt – Q 
ku K
km Q 1 – e – k m t 1 – e – k mu t
X m =   –  or
( k mu – k m ) k m k mu
Q X
k m Q 1 – e –Kt 1 – e –K1t
Xm = 
  – 
( K1 – K ) K K1
km
Xm kmu Xmu
dX
 = Q – k m X
dt
Q
sX – Xo =  – k m X
s
Q
sX + k m X = 
s
Q
X ( s + k m ) = 
s
Q
X = 
s ( s + km )
– kmt
(1 – e )
X = Q 
km
dX
m = k m X – k mu X m
dt
sX m – Xo = k m X – k mu Xm
sX m = k m X – k mu Xm
km Q
X m = 
s ( s + k mu ) ( s + k m )
sX mu – Xomu = k mu X m substitute X m
k mu k m Q
Q X mu = 
2

X s ( s + k m ) ( s + k mu )
k mu k m Qt k mu k m Q ( 1 – e –kmut ) ( 1 – e – k mt )
km X mu =  –   –  or
k m ⋅ k mu k m – k m u k
2
k
2
mu m
dX
 = Q – k m X
dt
Q
sX – Xo =  – k m X
s
Q
sX + k m X = 
s
Q
X ( s + k m ) = 
s
Q
X = 
s ( s + km )
dX
m = k m X – k mu X m
dt
sX m – Xo = k m X – k mu Xm
sX m + k mu X m = k m X
km Q
X m ( s + k mu ) = 
s ( s + km )
km Q
X m = 
s ( s + k m ) ( s + k mu )
k m Q 1 – e –kmut 1 – e –kmt
X m =   – 
k m – k mu k mu k m
sX – Xo = – k u X – k m X
sX + k u X + k m X = X o
X ( s + ku + km ) = Xo
Xo
X = 
( s + k u + km )
K = ( ku + km )
k mu = K1
Xo
X = 

(s + K)
– Kt
X = Xo e
Dose
km1
X ku Xu
km2
kmu2 Xmu2
Xm2
dX
 = – k u X – k m1 X – k m2 X
dt
sX – Xo = – k u X – k m1 X – k m2 X
sX + k u X + k m1 X + km2 X = Xo
Xo
X = 

(s + K)
K = ( k u + k m1 + k m2 ) and K1 = k mu1
dXm1

 = k m1 X – K1X m1
dt
sX m1 – Xm1o = k m1 X – K1X m1
X m1o = 0
k m1 Xo
sX m1 + K1X m1 = 

(s + K)
Q
simplified yields: C = 

KVd
dX
a = Q – k a X a
dt
Q
sX a – Xao =  – k a Xa
s
X a0 = 0
sX a + k a Xa = ( Q ⁄ s )
X a ( s + ka ) = ( Q ⁄ s )
Q
X a = 
s(s + ka)
– kat
Q( 1 – e )
X a = 
ka
dX
 = k a X a – KX
dt
sX – Xo = k a Xa – KX
Xo= 0
ka Q
sX + KX = 
s ( s + ka )
ka Q
X ( s + K ) = 

s ( s + ka )
ka Q
X = 

s ( s + ka ) ( s + K )
dX
 = – KX
dt
Dose
sX – Xo = – KX
Q sX + KX = X o
X
X ( s + K )= Xo
km
Xo
X = 

s+K
Xm kmu Xmu
dX m
 = k m X – K1X m
dt
dX sX m – Xo = k m X – K1X m
 = Q – KX
dt
Q sX m + K1X m = k m X
sX – Xo =  – KX
s
km X o
X m ( s + K1 ) = 
Q s+K
sX + KX = 
s
km Xo
Q X m = 
X ( s + K ) =  ( s + K1 ) ( s + K )
s
km Xo – Kt – K 1t
Q (e – e
X m =  )
X =  ( K1 – K )
s( s + K )
Thus,
dX
m = k m X – K1X m km X o
X m =  ( e – e
dt – Kt – K 1t
) + …
( K1 – K )
sX m – Xo = k m X – K1Xm
k m Q ( 1 – e –Kt ) ( 1 – e –K1t )
sX m + K1X m = k m X   – 
K1 – K K K1
km Q
X m ( s + K1 ) = 

s( s + K )
km Q
X m = 

s ( s + K1 ) ( s + K )
ku Xu dX mu k mu k m Xo –K1t – Kt
X {e
 = k mu Xm =  –e }
dt ( K – K1 )
dX dX mu k mu k m X o
 = k u ( X o e ) + 
 { e – e }
– Kt –K1t – Kt
km u + 
dt dt ( K – K1 )
Xm kmu Xmu
dX
 = – k u X – k m X
dt
sX – Xo = – k u X – k m X
sX + k u X + k m X = X o
X ( s + ku + km ) = Xo
( ku + km ) = K
Xo
X = 
(s + K)
– Kt
X = Xo e
dX
u = k m X = k u ( Xo e –Kt )
dt
dX
m = k m X – K1X m
dt
sX m – Xo = k m X – k1Xm
km Xo
sX m + K1X m = 

(s + K)
OBJECTIVES
After completing this chapter, the student will be able to:
1. Given patient data of the following types, the student will be able to properly con
struct (III) a graph and compute (III) the slope using linear regression: response
(R) vs. concentration (C), response (R) vs. time (T), concentration (C) vs. time (T)
2. Given any two of the above data sets, the student will be able to compute (III) the
slope of the third by linear regression.
3. Give response vs. time and response versus concentration data, the student will be
able to compute (III) the terminal (elimination) rate constant and half life of the
drug.
[ D ]E max
E = 
 (EQ 434)
KR + [D ]
If E is plotted against [D] a hyperbolic curve will result; the asymptote will be
E
0.4
0.2
E max .
0.0
0.0 0.8 1.6 2.4 3.2 4.0
D
a. If linear pharmacokinetics hold, the molar concentration of free drug at the
active site is proportional to the plasma concentration of the drug once equilibrium
has been established. Hence, a plot of E against Cp will also be hyperbolic.
c. For a series of doses the value of X at the same given time after dosing is propor
tional to the dose (D). Thus, a plot of E against D will also be hyperbolic at a spe
cific time.
0.4
0.2 this is the clinical range of responses, linear equations may be written. For exam
0.0 ple,
10 810710 610510 4103102101
Plot of Response vs. This example equation shows that, in the clinical range, the intensity of a pharma
Ln(C) is a straight line in cological response is proportional to the logarithm of the administered dose, pro
the middle (if you viding response is measured at a consistent time after dosing. The proportionality
squint), but only
between 20% and 80%
constant (slope, m ) is a function of the affinity of the drug for the receptor. In fact,
maximum response equation 435 yields a logdose response plot. Note that doubling the dose does not
double the response.
Pharmacological Response (R), Concentration (C), and Time (t) are interrelated.
The response and concentration relationship is studied in pharmacology. The con
centration and time relationship is studied in pharmacokinetics. The response and
time relationship is applied in therapeutics.
Remember: Use only You should know what the various graphical relationships look like. Response vs.
the data between 20% natural log of concentration is sigmoidal. (S shaped). We are interested in the mid
and 80% of maximum dle almost straight part. The slope is dR ⁄ d ln c .
response for the straight
part of both response
vs. Ln(c) and response Response vs. time is a straight line. The slope is dR ⁄ dt .
vs. t.
Natural log of concentration vs. time (drug given by IV bolus) is a straight line.
The slope is d ln c ⁄ dt .
You should be able to obtain the slope of each of these relationships from data sets.
You should be able to obtain the third slope’s relationship given the other two (or
data sets with which to get the other two).
dR dR d
ln c (EQ 436)
 =  ⋅
dt d ln c dt
dR  dR ⁄ dt
 =  (EQ 437)
d ln c d ln c ⁄ dt
d
ln c dR ⁄ dt
=  (EQ 438)
dt dR ⁄ d ln c
NOTE: Only between You should be able to apply the equation y = mx + b to each of the above relation
20% and 80% of maxi ships. Given the slope (or having obtained the slope) and two of the three variables
mum response!!!!!! (y, x, b), you should be able to find the third.
or
Ln ( X ) = Ln ( D ) – Kt (EQ 440)
Substituting twice from eq. 435 once at time t and once at zero time
E – b E 0–b
 =  – Kt → E = E0 – Rt (EQ 441)
m m
Rearranging,
ln 
D
X eff
t dur =  (EQ 443)
K
ln ( Dose ) ln ( Xeff )
t dur =  – 
 (EQ 444)
K K
Thus a plot of duration of action vs ln dose would result in a straight line with a
ln ( X ef f )
slope of 1/K and an x intercept of –  .
K
R
e. Calculate K =  .
m
t 1 ⁄ 2 = 
0.693
f. Calculate K
.
Thus a plot of E against X1 (or E against Cp ) will show a hysteresis loop with time,
most noticeably during an intravenous infusion.
DRUG RANGE
digoxin 0.82.0 ng ⁄ ml
gentamicin 210 µg ⁄ ml l
lidocaine 14 µg ⁄ ml
lithium 0.41.4 mEq ⁄ L
phenytoin 1020 µg ⁄ ml
phenobarbitol 1030 µg ⁄ ml
procainamide 48 µg ⁄ ml
quinidine 36 µg ⁄ ml
theophylline 1020 µg ⁄ ml
If we were to give an identical dose of drug to a large group of patients and then
measure the highest plasma drug concentration we would see that due to individual
variability, the resulting plasma drug concentrations differ. This variability can be
attributed to factors influencing drug absorption, distribution, metabolism, and
excretion. Therefore, drug dosage regimens must take into account any disease
altering state or physiological difference in the individual.
The major potential advantages of therapeutic drug monitoring are the maximiza
tion of therapeutic drug benefits and the minimization of toxic drug effects. The
formulation of drug therapy regimens by therapeutic drug monitoring involves a
process for reaching dosage decisions.
The data in Table 418 are population averages. Most people respond to drug con
centrations in these ranges. There is always the possibility that the range will be
different in an individual patient.
1. Nagashima, R., O’Reilly, RA., and Levy, G, Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin. Clin.
Pharm. Therap, 10 2235 (1969).
3. Gibaldi M. and Levy, G. Dosedependent decline of pharmacologic effects of drugs with linear pharmacokinetics characteristics.
J.Pharm.Sci, 61, 567569 (1972).
4. Brunner, L., Imhof, P., and Jack, D. Relation between plasma concentrations and cardiovascular effects of oral oxprenolol in
man. Europ. J. Clin. Pharmacol., 8, 39 (1975).
5. Galeazzi, R.L., Benet, L.Z., and Sheiner, L.B. Relationship between the pharmacokinetics and pharmacodynamics of procaina
mide. Clin. Pharm. Therap., 20, 67681 (1976).
6. Joubert, P., et al. Correlation between electrocardiographic changes, serum digoxin, and total body digoxin content. Clin.
Pharm. Therap., 20, 676681 (1976).
7. Amery, A., et al. Relationship between blood level of atenolol and pharmacologic effect. Clin. Pharm. Therap., 21, 691699
(1977).
3.4 Problems
What to do.> We want to get pharmacokinetic data (elimination rate con
stant) from pharmacological response data (Response vs concontration and
Response vs time graphs) .
0.6
dR
14. Find the slope of the straight line,  , (eyeball the rise over the run or use linear regression as
0.4 dT
0.2
required). Important: you must determine the best fit line through all of the points that you will
use. Eyeball method: Get the line as close to the points as possible placing as many points
0.0
10 10 10 10 10 10
above the line as below the line. Take two points on the line (not data points) to calculate the
Time
change in Y over the change in X.
10010
10010
10 10
1
1.0
10
0.8
0
0.6
Response
0.4
0.2
Response
0.0
1010
10810710610510 410310 2101
Conc.
1
Concentration
1
10
0 1
What we are attempting to do is get the logarithm part of the paper on the x axis and have the
numbers get bigger as you go from left to right.
15. Plot concentration on the x axis and response on the y.
16. Find the slope of the line plotted this way by the rise over the run method.
Run is change in ln(C).
If you take any two concentrations such that C2 = 2*C1 then the run is (ln(C2)  ln(C1)).
Using rules of logs, when two logs are subtracted, the numbers are devided, thus: = ln(C2/C1).
If C2 = 2*C1 then ln(C2/C1) = ln(2) = 0.693.
100
10
Concentration
1010
110
0 1
Time
18. Find the slope as before, using semi log paper (Remeber the log is on the Y axis this time, so
you find two concentrations such that c2 = 2*c1 and put it in the rise this time. Thus the slop of
rise 0.693 0.693
the line is m =  =  =  = – k
run t2 – t1 –t1

2
3.5 Oxpranolol
Brunner et al, Europ. J. Clin. Pharmacol., 8, 39 (1975).
In humans, the pharmacological response to oxpranolol (a beta blocker) is a decrease in beats per minute (bpm) com
pared to placebo during physical exercise. The following approximate mean data is from 7 healthy volunteers: beats per
minute (bpm) altered with time (t) after oral administration of three doses (D).
TABLE 419
Response vs Response vs
Concentration time
C p 
ng
Time (min) ml
30 699
60 622
120 413
150 292
240 152
360 60
480 24
1. Calculate the half life ( t 1 ⁄ 2 ) of oxpranolol from the pharmacological response table.
2. Plot plasma concentration data on Cartesian graph paper directly as well as transforming Cp into ln C p .
3. Plot plasma concentration data on semilog paper. Use linear regression to find the rate constant of elimination of
oxpranolol.
4. Calculate the half life obtained from the concentration data and compare it with the half life calculation based on the
pharmacological response.
Minoxidil (Problem 4  1)
Minoxidil is a potent antihypertensive which lowers the mean arterial blood pressure (MAP) in certain patients.
dR
1. Graph and find  (slope of (R)esponse vs. ln(C)oncentration graph).
d ln C
dR
2. Graph and find  (slope of (R)esponse vs. (T)ime graph).
dt
dR

dt
3. Find the ln(C)oncentration vs. (T)ime slope :  : Note that your slope m = – K . If you are having problems
dR

d ln C
understanding this, refer to Sections 2.4.2 2.4.4. K is the elimination rate constant.
4. Calculate t 1 ⁄ 2 = 0.693
 .
K
Propranolol (Problem 4  4)
Citation?
Beta blockers can be considered first line drugs of choice in the treatment of hypertension in certain patients. The fol
lowing data was obtained regarding Propranolol used to treat hypertension in a group of patients.
20 50
16 40
11 30
5 20
dR
1. Graph and find  (slope of (R)esponse vs. ln(C)oncentration graph).
d ln C
dR
2. Graph and find  (slope of (R)esponse vs. (T)ime graph).
dt
dR

dt
3. Find the ln(C)oncentration vs. (T)ime slope :  : Note that your slope m = – K . If you are having problems
dR

d ln C
understanding this, refer to Sections 2.4.2 2.4.4.
4. Calculate t 1 ⁄ 2 = 0.693
 .
K
Oxpranolol
22
20
Response (BPM)
18
16
14
12
10
1 2 3
10 10 10
Dose (mg)
TABLE 5.
X Y 2
ln(Dose) Dose Response X X⋅Y
3.689 40 10 13.61 36.89
4.094 60 13.5 16.76 55.27
4.382 80 16 19.20 70.11
4.787 120 19 22.92 90.96
5.075 160 21 25.75 106.58
ΣX = 22.03 ΣY = 79.5 2
ΣX = 98.25 ΣXY = 359.82
2
( ΣX ) = 485.23
ΣX Σy
)
dR 
 = 7.93 the slope is equal to the linear regression of the change in response vs. ln concentration.
d ln c
OXPRANOLOL
18
16
Response (BPM)
14
12
10
6
1.0 1.5 2.0 2.5 3.0 3.5 4.0
Time (hr)
1 R –R 2 16 – 10 dR
The slope of this plot is m =  =  = – 3.71 therefore,  = – 3.71 .
T1 – T 2 1.45 – 3.07 dt
dR

dt d ln c –3.71 –1 ln 2 0.693 
 =  = – k =  = – 0.4678hr t 1 ⁄ 2 =  =  = 1.48hr half life (89 min).
dR dt 7.93 k –1
 0.4678hr
d ln c
2. Plot plasma concentration data on Cartesian graph paper directly as well as transforming Cp into ln C p .
640
Concentration (ng/mL)
480
2
10
320
Concentration (ng/ml)
160
1
10
0 0 100 200 300 400 500
0 100 200 300 400 500
Time (min)
Time (min)
3. Plot plasma concentration data on semilog paper. Use linear regression to find the rate constant of elimination of
oxpranolol.
Using linear regression, as described above, the elimination rate constant is approximately
R vs Ln(C)
80
60
40
20
0
10 10 10
Dose (mg)
dR
 = 32.96
d ln C
dR
2. Graph and find  (slope of (R)esponse vs. (T)ime graph).
dt
R vs T
75
70
65
60
55
50
45
20 25 30 35 40 45 50
Time (hr)
dR
 = – 0.91
dt
dR

dt
3. Find the ln(C)oncentration vs. (T)ime slope :  : Note that your slope m = – K .
dR

d ln C
–1
K = 0.028hr
–
0.91
= – ( 0.028 )
32.96
4. Calculate t 1 ⁄ 2 = 0.693
 .
K
t 1 ⁄ 2 = 
0.693 
– 1
= 24.75hr
0.028hr
20
15
10
0
10 10
dR
 = 16.36
d ln C
dR
2. Graph and find  (slope of (R)esponse vs. (T)ime graph).
dt
25
20
15
10
5
0 1 2 3 4 5 6
dR
 = – 2.93
dt
dR

dt
3. Find the ln(C)oncentration vs. (T)ime slope :  : Note that your slope m = – K .
dR

d ln C
–1
K = 0.179hr
–
2.93
= – 0.179
16.36
4. Calculate t 1 ⁄ 2 = 0.693
 .
K
t 1 ⁄ 2 = 
0.693 
– 1
= 3.87hr
0.179hr
OBJECTIVES
For an IV one compartment model plasma and urine:
1. Given patient drug and/or metabolite concentration, amount, and/or rate vs. time
profiles, the student will calculate (III) the relevant pharmacokinetic parameters
available from IV plasma, urine or other excreta data: e.g.
V d, K, k m, k r, AUC, AUMC, CL, MRT, t 1 ⁄ 2
2. The student will provide professional communication regarding the pharmacoki
netic parameters obtained to patients and other health professionals.
3. The student will be able to utilize computer programs for simulations and data
analysis.
4.1.1 PLASMA
Valid equations: ln C p = – K ⋅ t + ln C p 0 (EQ 41)
(Obtained from the
LaPlace transforms
ln X = – K ⋅ t + ln X0 (EQ 42)
derived from the
appropriate models
– Kt
derived from the C p = C p0 e (EQ 43)
pharmacokinetic
descriptions of the drug)
D
C p 0 =  (EQ 44)
Vd
t ½ = 0.693
 (EQ 45)
K
( ∞)
( Cp n + Cp n + 1 ) Cp last
AUC = ∫ Cp dt = Σ  ⋅ ∆t +  (EQ 46)
2 K
0
( ∞) t
( t n ⋅ Cp n ) + ( t n + 1 ⋅ Cp n + 1 ) Cp l ast ( t l ast ⋅ Cp last )
AUMC = ∫ t ⋅ C p dt = ∑ 
2
 ⋅ ∆t +  + 
K
2 K
(EQ 47)
0 0
MRT = AUMC
 (EQ 48)
AUC
Cl = K ⋅ Vd (EQ 49)
Utilization:
Can you determine the • You should be able to plot a data set Concentration vs. time on semilog yielding a straight line
slope and intercept from with slope = – K and an intercept of C p0 .
a graph? Plot the data
in table 4 1.on semilog
graph paper. Extrapo
late the line back to time TABLE 41 Nifedipine 25 mg IV bolus
= 0 to get Cp0. Find the
Cp
half life. Calculate the Time (hr) (mcg/L)
elimination rate con
2 139
stant.
4 65.6
6 31.1
8 14.6
FIGURE 41.
Does your Graph look FIGURE 41 Nifedipine IV Bolus (25 mg IV Bolus)
like this?
100 10 3
Concentration (mic/L)
Cp0 = 295 mic/L
K1 = 0.375 hr 1
Concentration (ng/mL)
10 2
50 1.85 hr
10 1
0 2 4 6 8
Time (hr)
Time (hours)
• You should be able to determine K. A plot of the data in TABLE 41 results in FIGURE 41
dy
Remember from high school algebra, the slope of any straight line is the rise over the run,  ,
dx
In the case of semilog graphs dy is the difference in the logarithms of the concentrations. Thus,
using the rules of logarithms, when two logs are subtracted, the numbers themselves are
divided. i.e. ln ( C1 ) – ln ( C2 ) = ln  . Thus if we are judicious in the concentrations that we
C1
C2
take, we can set the rise to a constant number. So, if we take any two concentrations such that
one concentration is half of the other (In FIGURE 41 above, we took 100 and 50), the time it
takes for the concentration to halve is the half life (in the graph above, 1.85 hr). Then
0.693 0.693 –1
K =  =  = 0.375 hr
t½ 1.85hr
• You should be able to determine V d :. To do this, extrapolate the line to t = 0 . The value of Cp
mic
when t = 0 is C p0 (in the graph above, C p0 = 295  which is equal to D ⁄ V d for an IV bolus
L
dose only.
Dose 25mg ⋅ 1000mic
Thus, Cp 0 =  , V d = Dose
 =   = 85L
Vd Cp 0 295mic mg

L
The volume of distribution is a mathematical construct. It is merely the proportionality constant
between two knowns  the C p0 which results from a given D 0 . It is, however, useful because it
is patient specific and therefore can be used to predict how the patient will treat a subsequent
dose of the same drug. You should be able to obtain the volume of distribution from graphical
analysis of the data. Pay attention to the units! Make sure that they are consistent on both sides
of the equation. NOTE: the volume of distribution is not necessarily any physiological space.
For example the approximate volume of distribution of digoxin is about 600 L If that were a
physiological space and I were all water, that would mean that I would weigh about 1320
pounds. I’m a little overweight (I prefer to think that I’m underheight), but REALLY!
• Given any three of the variables of the IV bolus equation, either by direct information (the vol
ume of distribution is such and such) or by graphical data analysis, you should be able to find
the fourth.
• You should be able to calculate Area Under the Curve (AUC) from IV Bolus data (Time vs. Cp).
From the above data in TABLE 41 the AUC is calculated using (EQ 46):
(∞)
Cpn + Cp n + 1 Cp
AUC = ∫ Cp dt = Σ  + l which in this case is:
∆t K
0
295 + 139 139 + 65.6 65.6 + 31.1 31.1 + 14.6 14.6 mcg
Σ  ⋅ 2 +  ⋅ 2 +  ⋅ 2 +  ⋅ 2 +   hr or
2 2 2 2 0.375 L
mcg mcg
Σ { 434 + 204.6 + 96.7 + 45.7 + 38.9 }  hr = 819.9  hr . In tabular format, the AUC calculation
L L
is shown in TABLE 42.
t t
AUC AUC
TIME Cp t–1 0
0 295
2 139 434.0 434.0
4 65.6 204.6 638.6
6 31.1 96.7 735.3
8 14.6 45.7 781.0
∞ 0 38.9 819.9
The AUC of a plot of plasma concentration vs. time, in linear pharmacokinetics, is a number
which is proportional to the dose of the drug which gets into systemic circulation. The propor
tionality constant, as before, is the volume of distribution. It is useful as a tool to compare the
amount of drug obtained by the body from different routes of administration or from the same
route of administration by dosage forms made by different manufacturers (calculate bioavail
ability in subsequent discussions).
The AUC of a plot of Rate of Excretion of a drug vs. time, in linear pharmacokinetics, is the
mass of drug excreted into the urine, directly.
• You should be able to calculate the AUMC from IV Bolus data (Time vs. Cp). The equation for
AUMC is equation 47:
( ∞) t
( t n ⋅ Cp n ) + ( t n + 1 ⋅ Cp n + 1 ) Cp l ast ( t l ast ⋅ Cp last )
AUMC = ∫ t ⋅ C p dt = ∑ 
2
 ⋅ ∆t +  + 
K
2 K
which in the
0 0
data given in TABLE 41 is:
T0 ⋅ C po + T1 ⋅ C p1 T1 ⋅ C p1 + T2 ⋅ C p2 T 2 ⋅ C p 2 + T3 ⋅ C p3
Σ  ⋅ ∆t 1 +  ⋅ ∆t 2 +  ⋅ ∆t 3 +
2 2 2
mcg 2
Σ { 278 + 540.4 + 449 + 303.4 + 311.47 + 103.82 } = 1986.1  hr
L
Thus in tabular format the AUMC for data given in TABLE 41 is TABLE 43 below.
t
AUMC t AUMC
TIME Cp Cp*T 0
0 295 0
2 139 278 278.0 278.0
4 65.6 262.4 540.4 818.4
6 31.1 186.6 449.0 1267.4
8 14.6 116.8 303.4 1570.8
∞ 0 0 415.3 1986.1
The AUMC is the Area Under the first Moment Curve. A plot of T*Cp vs. T is the first
moment curve. The time function buried in this plot, the Mean Residence Time (MRT), can be
extracted using equation 48 below.
It is the geometric mean time that the molecules of drug stay in the body. It has utility in the fact
that, as drug moves from the dosage form into solution in the gut, from solution in the gut into
the body, and from the body out, each process is cumulatively additive. That means if we can
physically separate each of these processes in turn, we can calculate the MRT of each process.
The MRT of each process is the the inverse of the rate constant for that process.
• You should be able to calculate MRT from IV Bolus data (Time vs. Cp) using equation 48
AUMC 1986.1
MRT =  =  = 2.42
AUC 819.9
Since there is only the process of elimination (no release of the drug from the dosage form, no
absorption), the MRT is the inverse of the elimination rate constant, K. Thus MRT = 1/K.
K
X
MRT(IV) = 1/K
Suppose the drug were given in a solution. Then the drug would have to be absorbed and then
eliminated. Since the MRTs are additive, the MRT of the oral solution would be made up of the
MRTs of the two processes, thus:
Ka K
Xa X
MRT(os) = MAT(os)+MRT(IV)
MRT(os) = 1/Ka + 1/K
Consequently, if a drug has to be released from a dosage form for the drug to get into solution
which is subsequently absorbed, a tablet for example, the MRT of the tablet will consist of the
MRT(IV) and the MAT(os) and the Mean Dissolution Time (MDT), thus:
Kd Ka K
Xd Xa X
Normally, we don’t have information from the oral solution, just IV and tablet. So in that case
the information obtained about absorption from the tablet is bundled together into an apparent
absorption rate constant consisting of both dissolution and absorption.
It should be apparent that this is a reasonably easily utilized and powerful tool used to obtain
pharmacokinetic parameters.
1
3. MRT =  ( estimate ) MRT = AUMC
 equation 48
K AUC
Cp ∞
5. Estimate for AUC = AUC = 0 which is
K ∫0 Cp dt
(∞)
( Cp n + Cp n + 1 ) Cp last
AUC = ∫ Cp dt = Σ  ( ∆t ) + 
2 K
0
( ∞) t
( t n ⋅ Cp n ) + ( t n + 1 ⋅ Cp n + 1 ) Cp last ( t last ⋅ Cp l ast )
AUMC ∫ Cp dt = ∑ 
2
 ⋅ ∆t n +  + 
K
2 K
0 0
7. V d = Dose
 from equation 44
Cp 0
Cp 0 Dose
8. Cl = K1 ⋅ V d =  ⋅  = Dose

AUC Cp 0 AUC
Acyclovir (Problem 4  1)
Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
De Miranda and Burnette, “Metabolic Fate and Pharmacokinetics of the Acyclovir Prodrug Valaciclovir in Cynomolgus Mon
keys”, Drug Metabolism and Disposition (1994): 5559.
Acyclovir is an antiviral drug used in the treatment of herpes simplex, varicella zoster, and in suppressive therapy. In
this study, three male cynomolgus monkeys were each given a 10 mg ⁄ kg intravenous dose. The monkeys weighed an
average of 3.35 kg each. Blood samples were collected and the following data was obtained:
PROBLEM TABLE 4  1. Acyclovir
Serum concentration
Time (hours) ( µg ⁄ mL )
0.167 26.0
0.300 23.0
0.500 19.0
0.75 16.0
1.0 12.0
1.5 7.0
2.0 5.0
From the data presented in the Preceding table, determine the following:
1. Find the elimination rate constant, k .
3. Find MRT .
4. Find ( C p )0 .
(Problem 4  1) Acyclovir:
2
10
CONCENTRATION (MIC/ML)
1
10
100
0.0 0.5 1.0 1.5 2.0
TIME (HR)
–1
1. k = 0.93hr
2. t½ = 0.75hr .
3. MRT = 1.08hr .
4. ( C p )0 = 30.4ug ⁄ mL .
5. AUC = 32.75ug ⁄ mL ⋅ hr .
2
6. AUMC = 35.2ug ⁄ mL ⋅ hr .
7. Vd = 1.1L
8. Cl = 1.02L ⁄ hr .
Aluminum (Problem 4  2)
Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Xu, Pai, and Melethil, "Kinetics of Aluminum in Rats. II: DoseDependent Urinary and Biliary Excretion", Journal of Pharmaceu
tical Sciences, Oct 1991, p 946  951.
A study by Xu, Pai, and Melethil establishes the pharmacokinetics of Aluminum in Rats. In this study, four rats with an
average weight of 375g, were given an IV bolus dose of aluminum (1 mg/kg). Blood samples were taken at various
intervals and the following data was obtained:
PROBLEM TABLE 4  2. Aluminum
ng
Serum concentration, 
Time (hours) mL
0.4 19000
0.6 18000
1.4 15000
1.6 14500
2.3 12500
3.0 10500
4.0 8500
5.0 6500
6.0 5000
8.0 3250
10.0 2000
12.0 1250
From the data presented in the preceding table, determine the following:
3. Find MRT .
4. Find ( C p )0 .
(Problem 4  2) Aluminum:
5
10
CONCENTRATION (NG/ML)
4
10
3
10
0 2 4 6 8 10 12
TIME (HR)
–1
1. k = 0.234hr
2. t½ = 3hr .
3. MRT = 4.3hr .
4. ( C p )0 = 21000ng ⁄ mL .
5. AUC = 89285ng ⁄ mL ⋅ hr .
2
6. AUMC = 383926ng ⁄ mL ⋅ hr .
7. Vd = 17.86mL
8. Cl = 4.18mL ⁄ hr .
Amgen (Problem 4  3)
Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Salmonson, Danielson, and Wikstrom, "The pharmacokinetics of recombinant human erythropoetin after intravenous and subcuta
neous administration to healthy subjects", Br. F. clin. Pharmac. (1990), p 709 713.
Amgen (rEpo) is a form of recombinant erythropoetin. Erythropoetin is a hormone that is produced in the kidneys and
used in the production of red blood cells. The kidneys of patients who have endstage renal failure cannot produce
erythropoetin; therefore, rEpo is being investigated for use in these patients in order to treat the anemia that results
from the lack of erythropoetin. In a study by Salmonson et al, six healthy volunteers were used to demonstrate that
both IV and subcutaneous administration of erythropoetin have similar effects in the treatment of anemia due to
chronic renal failure. The six volunteers were each given a 50 U/kg intravenous dose of Amgen. The average weight
of the six volunteers was 79 kg. Blood samples were drawn at various times and the data obtained is summarized
below:
PROBLEM TABLE 4  3. Amgen
mU
Serum concentration, 
Time (hours) mL
2 700
4 600
6 400
8 300
12 150
24 40
From the data presented in the preceding table, determine the following:
3. Find MRT .
4. Find ( C p )0 .
(Problem 4  3) Amgen:
103
CONCENTRATION (MU/ML)
102
Con (mU/mL)
101
0 5 10 15 20 25
TIME (HR)
–1
1. k = 0.134hr
2. t½ = 5.2hr .
3. MRT = 7.46hr .
4. ( C p )0 = 900mU ⁄ mL .
5. AUC = 6945mU ⁄ mL ⋅ hr .
2
6. AUMC = 49600 mU ⁄ mL ⋅ hr .
7. Vd = 4.44L
8. Cl = 0.6L ⁄ hr .
A study by Brier and Harding a dose of 45 ng was given by IV bolus to rats. Samples of blood were taken at various
intervals throughout the length of the study and the following data was obtained:
PROBLEM TABLE 4  4. Atrial Naturetic Peptide (ANP)
pg
Serum concentration, 
Time (minutes) mL
3 380
10 280
20 170
30 130
40 100
50 70
60 50
From the data presented in the preceding table, determine the following:
1. Find the elimination rate constant, k .
3. Find MRT .
4. Find ( C p )0 .
103
Con CONCENTRATION (PG/ML)
102
(pg/mL)
101
0 10 20 30 40 50 60
Time (min)
–1
1. k = 0.0345min
2. t½ = 20.09min .
3. MRT = 28.95min .
4. ( C p )0 = 386.6pg ⁄ mL .
8. Cl = 4.02mL ⁄ min .
Aztreonam (Problem 4  5)
Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Cuzzolim et al., "Pharmacokinetics and Renal Tolerance of Aztreonam in Premature Infants", Antimicrobial Agents and Chemo
therapy (Sept. 1991), p. 1726  1928.
Aztreonam is a monolactam structure which is active against aerobic, gramnegative bacilli. The pharmacokinetic
parameters of Aztreonam were established in a study presented in by Cuzzolim et al in which Aztreonam (100 mg/ kg)
was administered intravenously to 30 premature infants over 3 minutes every 12 hours. The group of neonates had an
average weight of 1639.6g. The following set of data was obtained:
PROBLEM TABLE 4  5. Aztreonam
µg
Serum concentration, 
Time (minutes) mL
1 40.50
2 34.99
3 29.99
4 23.88
5 22.20
6 19.44
7 16.55
8 14.99
From the data presented in the preceding table, determine the following:
1. Find the elimination rate constant, k .
3. Find MRT .
4. Find ( C p )0 .
(Problem 4  5) Aztreonam:
10 2
CONCENTRATION (UG/ML)
Con (ug/mL)
10 1
0 2 4 6 8
TIME (MIN)
–1
1. k = 0.144min
2. t½ = 4.81min .
3. MRT = 6.94min .
4. ( C p )0 = 45.75ug ⁄ mL .
8. Cl = 0.516L ⁄ min .
Bovine placental lactogen (bPL) is a hormone similar to growth hormone and prolactin. It binds to both prolactin and
growth hormone receptors in the rabbit and stimulates lactogenesis in the rabbit. In a study by Byatt, et. al., four cows
(2 pregnant and 2 nonpregnant) were given IV bolus injections of 4 mg and the following data was obtained:
PROBLEM TABLE 4  6. Recombinant Bovine Placental Lactogen
µg
Serum concentration 
Time (minutes) L
3.8 117
6.8 72
12.0 43
16.0 27
20.0 18
From the data presented in the preceding table, determine the following:
3. Find MRT .
4. Find ( C p )0 .
(MIC/L)
ConCONCENTRATION
102
(ug/L)
101
0 5 10 15 20
Time (min)
–1
1. k = 0.113min
2. t½ = 6.13min .
3. MRT = 8.85min .
4. ( C p )0 = 167.8ug ⁄ L .
8. Cl = 2.69L ⁄ min .
Caffeine (Problem 4  7)
Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Dorrbecker et. al., "Caffeine and Paraxanthine Pharmacokinetics in the Rabbit: Concentration and Product Inhibition Effects.",
Journal of Pharmacokinetics and Biopharmaceutics (1987), p.117  131.
This study examines the pharmacokinetics of caffeine in the rabbit. In this study type I New Zealand White rabbits
were given an 8 mg intravenous dose of caffeine. Blood samples were taken and the following data was obtained:
PROBLEM TABLE 4  7. Caffeine
µg
Serum concentration 
Time (minutes) mL
12 3.75
40 2.80
65 2.12
90 1.55
125 1.23
173 0.72
243 0.37
From the data presented in the preceding table, determine the following:
1. Find the elimination rate constant, k .
3. Find MRT .
4. Find ( C p )0 .
(Problem 4  7) Caffeine:
CONCENTRATION (MIC/ML)
Caffeine
101
100
101
Con (ug/L)
Time (min)
–1
1. k = 0.00997min
2. t½ = 69.51min .
3. MRT = 100.3min .
4. ( C p )0 = 4.105ug ⁄ mL .
8. Cl = 19.44mL ⁄ min .
Ceftazidime (Problem 4  8)
Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
DemotesMainard, et. al., "Pharmacokinetics of Intravenous and Intraperitoneal Ceftazidime in Chronic Ambulatory Peritoneal
Dyialysis", Journal of Clinical Pharmacology (1993), p. 475  479.
Ceftazidime is a third generation cephalosporin which is administered parenterally. In this study, eight patients with
chronic renal failure were each given 1 g of ceftazidime intravenously. Both blood samples were taken the data
obtained from the study is summarized in the following table:
mg
Serum concentration 
Time (hours) L
1 50
2 45
4 38
24 21
36 14
48 11
60 8
72 4
From the data presented in the preceding table, determine the following:
3. Find MRT .
4. Find ( C p )0 .
(Problem 4  8) Ceftazidime:
102
CONCENTRATION (MG/L)
101
Con (mg/L)
100
0 20 40 60 80
Time (hours)
–1
1. k = 0.0324hr
2. t½ = 21.39hr .
3. MRT = 30.86hr .
4. ( C p )0 = 47.57mg ⁄ L .
5. AUC = 1468.2mg ⁄ L ⋅ hr .
2
6. AUMC = 45308.6mg ⁄ L ⋅ hr .
7. Vd = 21.02L
8. Cl = 0.681L ⁄ hr .
Ciprofloxacin (Problem 4  9)
Problem Submitted By: Maya Lyte AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 1234567890 Antivirals
Lettieri, et. al., "Pharmacokinetic Profiles of Ciprofloxacin after Single Intravenous and Oral Doses", Antimicrobial Agents and
Chemotherapy (May 1992), p. 993 996.
Ciprofloxacin is a fluoroquinolone antibiotic which is used in the treatment of infections of the urinary tract, lower res
piratory tract, skin, bone, and joint. In this study, twelve healthy, male volunteers were each given 300 mg intravenous
doses of Ciprofloxacin. Blood and urine samples were collected at various times throughout the day and the following
data was collected:
PROBLEM TABLE 4  9. Ciprofloxacin
mg
Serum concentration 
Time (hours) L
2 1.20
3 0.85
4 0.70
6 0.50
8 0.35
10 0.25
From the data presented in the preceding table, determine the following:
3. Find MRT .
4. Find ( C p )0 .
(Problem 4  9) Ciprofloxacin:
101
CONCENTRATION (MG/L)
100
Con (mg/L)
101
0 2 4 6 8 10
Time (hours)
–1
1. k = 0.1875hr
2. t½ = 3.7hr .
3. MRT = 5.33hr .
4. ( C p )0 = 1.57mg ⁄ L .
5. AUC = 8.395mg ⁄ L ⋅ hr .
2
6. AUMC = 44.74mg ⁄ L ⋅ hr .
7. Vd = 190.6L
8. Cl = 35.74L ⁄ hr .
Diprophylline is used as a bronchodilator. A study by Nadai et al was designed to determine whether or not coadmin
istration of Diprophylline with Probenecid affected the pharmacokinetic parameters of Diprophylline. In this study,
male rats (average weight: 300 g) were given 60 mg/kg of Diprophylline intravenously and a 3 mg/kg loading dose of
Probenecid followed by a continuous infusion of 0.217 mg/min/kg of Probenecid. The following set of data was
obtained for Diprophylline (DPP):
µg
Serum concentration 
Time (minutes) mL
16 40.00
31 27.00
60 13.00
91 6.50
122 3.50
From the data presented in the preceding table, determine the following:
3. Find MRT .
4. Find ( C p )0 .
102
CONCENTRATION (MIC/ML)
101
Con (ug/mL)
100
0 20 40 60 80 100
Time (min)
–1
1. k = 0.023min
2. t½ = 30.13min .
3. MRT = 43.48min .
4. ( C p )0 = 55.13ug ⁄ mL .
8. Cl = 7.5mL ⁄ min .
Epoetin is recombinant human erythropoetin. Erythropoetin is a hormone that is produced in the kidneys and used in
the production of red blood cells. The kidneys of patients who have endstage renal failure cannot produce erythropo
etin; therefore, Epoetin is used in these patients to treat the anemia that results from the lack of erythropoetin. Epoetin
has also been used in the treatment of anemias resulting from AIDS. malignant disease, prematurity, rheumatoid arthri
tis, sicklecell anemia, and myelosplastic syndrome. In a study by Macdougall et al, eight patients who were on perito
neal dialysis (CAPD) were given an IV bolus dose of 120 U/kg which decayed monoexponentially from a peak of 3959
U/L to 558 U/L at 24 hours. The following data was obtained:
PROBLEM TABLE 4  11. Epoetin
U
Serum concentration 
Time (hours) L
0.0 4000
0.5 3800
1.0 3600
2.0 3300
3.0 3000
4.0 2550
5.0 2350
6.0 2150
7.0 1900
From the data presented in the preceding table and assuming that the patient weighs 65 kg, determine the following:
3. Find MRT .
4. Find ( C p )0 .
104
CONCENTRATION (U/L)
Con (U/L)
103
0 1 2 3 4 5 6 7
Time (hours)
–1
1. k = 0.107 hr
2. t½ = 6.5 hr .
3. MRT = 9.38 hr .
4. ( C p )0 = 4023 Units/L .
Units ⋅ hr
5. AUC = 37775  .
L
2
Units ⋅ hr
6. AUMC = 354697  .
L
7. Vd = 1.9 L
L
8. Cl = 0.2065  .
hr
Famotidine is a histamine H2receptor antagonist. The study by Kraus, et. al., focuses on the kinetics of famotidine in
children. In the study, ten children with normal kidney function and a body weight ranging from 14  25 kg, were each
given a single intravenous 0.3 mg/kg dose of famotidine. Blood and urine samples were taken providing the following
data:
PROBLEM TABLE 4  12. Famotidine
µg
Serum concentration 
Time (hours) L
0.33 300
0.50 250
1.00 225
4.00 125
8.00 70
12.00 40
16.00 15
From the data presented in the preceding table, determine the following assuming that the patient weighs 17.2 kg:
3. Find MRT .
4. Find ( C p )0 .
10 3
(MIC/L)
ConCONCENTRATION
10 2
(ug/mL)
10 1
0 5 10 15 20
Time (hours)
–1
1. k = 0.17 hr
2. t½ = 3.9 hr .
3. MRT = 5.7 hr .
µg
4. ( C p )0 = 285  .
L
µg ⋅ hr
5. AUC = 1600  .
L
2
µg ⋅ hr
6. AUMC = 9000  .
L
7. Vd = 18 L
8. Cl = 3.2L .
Ganciclovir (mw: 255.23) is used against the human herpes viruses, cytomegalovirus retinitis, and cytomegalovirus
infections of the gastrointestinal tract. In this study, twentyseven newborns with cytomegalovirus disease were given
4 mg/kg of ganciclovir intravenously over one hour. Blood samples were taken and the data obtained is summarized in
the following table:
From the data presented in the preceding table and assuming the patient weighs 3.6 kg, determine the following :
3. Find MRT .
4. Find ( C p )0 .
10
CONCENTRATION (MICMOLE/L)
10
10
0 2 4 6 8
TIME (HR)
–1
1. k = 0.288hr
2. t½ = 2.4hr .
3. MRT = 3.5hr .
µmole
4. ( C p )0 = 23  .
mL
µmole ⋅ hr
5. AUC = 80  .
mL
2
µmole ⋅ hr
6. AUMC = 280  .
mL
mg 1000µg
4  ⋅ 3.6kg ⋅ 
Dose kg mg
7. Vd =  =  = 2.45L
Cp 0 µmole µg
23  ⋅ 255.23 
L µmole
L
8. Cl = 0.7  .
hr
Imipenem is a betalactam antibiotic which is used in combination with cilastin and is active against a broad spectrum
of bacteria. The pharmacokinetics of Imipenem in pregnant women is established in this study. Twenty women (six of
which were nonpregnant controls) were given a single intravenous dose of 500 mg of imipenemcilastin (1:1). Blood
samples were taken at various intervals and the data obtained is summarized in the following table:
mg
Serum concentration 
Time (minutes) L
10 27.00
15 23.50
30 15.50
45 9.50
60 6.50
From the data presented in the preceding table, determine the following:
3. Find MRT .
4. Find ( C p )0 .
CONCENTRATION (MG/L)
1
10
0
10
0 10 20 30 40 50 60
TIME (MIN)
–1
1. k = 0.029 min
2. t½ = 24 min .
Methylprednisolone is a corticosteriod that has been used in combination chemotherapy for the treatment of hemato
logical malignancy, myeloma, and acute lymphoblastic leukemia. In a study by Patel et. al., eight patients were given
1.5 gram intravenous doses of methylprednisolone from which the following data was obtained:
µg
Serum concentration 
Time (hours) mL
0.5 19.29
1.0 17.56
1.8 15.10
4.0 9.98
5.8 7.10
8.0 4.70
12.0 2.21
18.0 0.71
24.0 0.23
From the data presented in the preceding table, determine the following:
3. Find MRT .
4. Find ( C p )0 .
102
CONCENTRATION (MIC/ML)
101
100
Con (ug/mL)
101
0 5 10 15 20 25
Time (hours)
–1
1. k = 0.188 hr
2. t½ = 3.69hr .
3. MRT = 5.3hr .
µg
4. ( C p )0 = 21.2  .
mL
µg ⋅ hr
5. AUC = 112.5  .
mL
2
µg ⋅ hr
6. AUMC = 598.4  .
mL
7. Vd = 71L
L
8. Cl = 13.3  .
hr
Omeprazole (mw: 345.42) is a gastric protonpump inhibitor which decreases gastric acid secretion. It is effective in
the treatment of ulcers and esophageal reflux. In normal patients 80% of the omeprazole dose is excreted as metabo
lites in the urine and the remainder is excreted in the feces. In the study by Anderson, et. al., eight patients with liver
cirrhosis were given 20 mg, IV bolus doses of omeprazole. The patients had a mean body weight of 70 kg. Both blood
were taken at various intervals throughout the study and the following data was obtained:
ρmole
Serum concentration 
Time (hours) mL
0.75 3.49
1.00 3.25
2.00 2.46
3.00 1.86
4.00 1.40
5.00 1.06
6.00 0.80
7.00 0.61
8.00 0.46
10.00 0.26
12.00 0.15
From the data presented in the preceding table, determine the following :
3. Find MRT .
4. Find ( C p )0 .
10 1
(umol/mL) (PICOMOLE/ML)
10 0
ConCONCENTRATION
101
0 2 4 6 8 10 12
Time (hours)
–1
1. k = 0.280hr
2. t½ = 2.5hr .
3. MRT = 3.57hr .
ρmole
4. ( C p )0 = 4.3  .
mL
ρmole ⋅ hr
5. AUC = 15.4  .
mL
2
ρmole ⋅ hr
6. AUMC = 55  .
mL
Dose 20mg
7. Vd =  =  = 13465L
Cp 0 ρmole mmole
4.3  ⋅   ⋅ 345.42mg
 ⋅ 1000mL

mL 10 ρmole mmole 9 L
L
8. Cl = 3.9  .
hr
Pentachlorophenol (PCP) is a general biocide. That is, it is an insecticide, fungicide, bactericide, herbicide, algaecide,
and molluskicide, that is used as a wood preservative. Extensive exposure to PCP can be fatal. In a study by Reigner
et al, six mice (average weight: 27 g) were given 15 mg/kg of PCP by intravenous bolus. Blood samples were taken at
various intervals from which the following data was obtained:
PROBLEM TABLE 4  17. Pentachlorophenol
µg
Serum concentration 
Time (hours) mL
0.083 38.00
4.000 22.00
8.000 14.00
12.000 7.90
24.000 1.30
28.000 0.75
32.000 0.60
36.000 0.40
From the data presented in the preceding table, determine the following :
1. Find the elimination rate constant, k .
3. Find MRT .
4. Find ( C p )0 .
CONCENTRATION (MIC/ML)
102
101
100
Con (ug/mL)
101
0 10 20 30 40
Time (hours)
–1
1. k = 0.134 hr
2. t½ = 5.2hr .
3. MRT = 7.5hr .
µg
4. ( C p )0 = 35.6  .
mL
µg ⋅ hr
5. AUC = 281  .
mL
2
µg ⋅ hr
6. AUMC = 2100  .
mL
7. Vd = 11.4mL
ml
8. Cl = 1.5  .
hr
µg
Serum concentration 
Time (minutes) mL
2.0 90.3
2.9 83.9
5.6 67.3
8.9 51.5
10.5 45.2
13.5 35.4
15.0 31.3
20.0 20.9
24.0 15.1
59.6 0.9
From the data presented in the preceding table, determine the following. (Assume that the mouse weighs 200g.)
3. Find MRT .
4. Find ( C p )0 .
10 2
ConCONCENTRATION (MIC/ML) 10 1
10 0
(ug/mL)
10 1
0 10 20 30 40 50 60
Time (min)
–1
1. k = 0.08min
2. t½ = 8.67min .
3. MRT = 12.5min .
µg
4. ( C p )0 = 105  .
mL
µg ⋅ hr
5. AUC = 1300  .
mL
2
µg ⋅ hr
6. AUMC = 16250  .
mL
7. Vd = 47.6ml
mL
8. Cl = 3.8  .
min
Thioperamide is a histamine (H3) receptorantagonist. In a study by Sakurai et al, rats were given 10 mg/kg intrave
nous injections of Thioperamide. The following data was obtained from the study:
PROBLEM TABLE 4  19. Thioperamide
µg
Serum concentration 
Time (minutes) mL
3.7 3.1
7.5 2.8
13 2.4
45 1.1
60 0.74
120 0.16
From the data presented in the preceding table, determine the following:
3. Find MRT .
4. Find ( C p )0 .
101
ConCONCENTRATION (MIC/ML)
100
(ug/mL)
101
0 20 40 60 80 100 120
Time (min)
–1
1. k = 0.0254min
2. t½ = 27.3min .
3. MRT = 39.4min .
µg
4. ( C p )0 = 3.39  .
mL
µg ⋅ min
5. AUC = 133.5  .
mL
2
µg ⋅ min
6. AUMC = 5256  .
mL
mg
10 
Dose kg L
7. Vd =  =  = 2.95 
Cp 0 µg mg 1000mL kg
3.39  ⋅  ⋅ 
mL 1000µg L
–1 L 1000ml mL
8. Cl = 0.0254min ⋅ 2.95  ⋅  = 75  .
kg L min ⋅ kg
Khan,vM. et. al. “Determination of pharmacokinetics of cocaine in sheep by liquid chromatography” J. Pharm. Sci. 76:1 (3943)
Jan 1987
4.1.3 URINE
k ( –K ⋅ t )
Xu = u ⋅ X0 ⋅ ( 1 – e ) (EQ 410)
K
k
( Xu )∞ – Xu = u ⋅ X 0 ⋅ e
– Kt
K
(EQ 411)
ku
where the amount of drug that shows up in the urine at infinite time, ( X u ) ∞ =  ⋅ X 0 .
K
Thus a plot of ( Xu )∞ – X u vs. time on semilog paper would result in a straight line
with a slope of K and an intercept of ( X u ) ∞ .. and we can get ku from the intercept
( X u )∞
and the slope. Rearranging the intercept equation, we get k u = K ⋅  This method
X0
of obtaining pharmacokinetic parameters is known as the Amount Remaining to be
Excreted (ARE) method.
TABLE 44 Enalapril urinary excretion data from 5 mg IV Bolus
Cumulative
∞
Enalapril in urine X – X u mg
Time (hr) (mg) u
1 0.41 0.59
2 0.65 0.35
3 0.80 0.20
4 0.88 0.12
6 0.96 0.04
∞ 1.0 
0.2
Xu(inf)  Xu
0.1
1
10
1.3 hr
half life
2
10
0 1 2 3 4 5 6
Hours
• You should be able to transform a data set containing amount of drug in the urine vs. time into
cumulative amount of drug in the urine vs. time and plot the ARE. (Amount Remaining to be
Excreted > { ( Xu )∞ – Xu ( cum ) } vs. time on semilog yielding a straight line with a slope of
–1 ku ⋅ X0
– K = – 0.533 hr and an intercept of ( Xu ) ∞ =  = 1.0 mg
K
• You should be able to determine the elimination rate constant, K1, from cumulative urinary
excretion data. (Calculate the slope of the graph on SL paper.)
• You should be able to determine the excretion rate constant, ku, from cumulation urinary excre
tion data. (Divide the intercept of the graph by X0 and multiply by K1.
( X u )∞ –1 1.0 mg –1
k u = K ⋅  = 0.53 hr ⋅  = 0.106 hr )
X0 5.0 mg
A second method is to plot the rate at which the drug shows up in the urine over
time. Again, using the LaPlace transforms, we find that:
dX u –K t –K t
 = k u ⋅ X0 ⋅ e = R0 ⋅ e (EQ 412)
dt
Utilization: Rate of Thus, a plot of the rate of excretion vs. time results in a straight line on semilog
excretion method paper with a slope of K1 and an intercept, R0 , of kuX0 . Rearranging the intercept
R
equation yields k u = 0 . In real data, we don’t have the instantaneous excretion
X0
dX u ∆X
rate , but the average excretion rate, u , over a much larger interval. What
dt ∆t
that means to our calculations is that over the interval of data collection, the total
amount of drug collected divided by the total time interval is the average rate. In
the beginning of the interval the rate was faster than at the end of the interval. So
the average rate must have occurred in the middle of the interval. Thus equation 4
12 which is the instantaneous rate can be rewritten to
∆Xu –K t
mid
–K t
mid
 = k u ⋅ X 0 ⋅ e = R0 ⋅ e (EQ 413)
∆t
TABLE 45 Enalapril Urinary Rate Data
Enalapril in ∆X
urine ∆X u ,(mg) u
Interval (hr) t(mid) ∆t ∆t
01 0.5 1 0.41 0.41
12 1.5 1 0.24 0.24
23 2.5 1 missed sample ?
34 3.5 1 0.08 0.08
46 5 2 0.08 0.04
• You should be able to transform a data set containing amount of drug in the urine vs. time inter
∆X
val into Average Rate, u , vs. t ,(t mid the time of the midpoint of the interval), on semilog
∆t
yielding a straight line with a slope of – K and an intercept of k u ⋅ X 0 . as shown below.
1
0
10
R0 = 0.53 mg/hr
Urinary Excretion Rate (mg/hr)
1
2
10
1.3 hr
half life
2
10
0 1 2 3 4 5
T (Mid)
• You should be able to determine k u extrapolate the line to t = 0 . The value of Rate (at
t = 0 ), R0, = k r ⋅ X0 = 0.53 ( mg ⁄ hr ) which when divided by X 0 .is kr.
R 0.53mg/hr –1
Thus, 0 =  = 0.106hr
X0 5mg
The rate equation is superior clinically because the ARE method requires collec
tion of all of the urine which is usually only possible when you have a catheterized
patient while the Rate Method does not. (People don’t urinate on command, and
your data could be in the toilet, literally.)
∞
An additional advantage of the rate equations is that the AUC has the units of
0
mass, which gives the total amount of drug excreted into the urine directly. Thus:
∞ R 0 0.53 mg/hr
AUC =  = 
–1
= 1 mg
0 K 0.53 hr
dX –K t –K t
u = k u ⋅ X 0 ⋅ e = R0 ⋅ e
dt
where ku is the rate constant through which the drug entered the urine and
dX –K t
 = X 0 ⋅ e is the equation of the previous compartment.
dt
4.2 Metabolite
4.2.1 PLASMA
– ( K l arg e ⋅ t )
km X 0 – ( Ksmall ⋅ t )
C pm =   e –e (EQ 414)
K l arg e – K small V dm
Utilization: • You should be able to plot a data set of plasma concentration of metabolite vs. time on semilog
Curve Stripping paper yielding a biexponential curve.
–k t –k t
– Kt l arg e small
e → 0 as t → ∞ . And e → 0 faster than e → 0 . So, at some long
–K t –K t –K t
l arg e small l arg e
time, t, e «e . In fact e is small enough to be ignored. Thus at long
time, t, the equation becomes :
km X0 –( Ksmall ⋅ t )
C pm = 
 
 e
K l arg e – K small V dm (EQ 415)
So that the plot of the terminal portion of the graph would yield a straight line with a slope of
km
 X0
Ksmall and an intercept of I =  

K l arg e – K small Vdm
• You should be able to obtain the slope of the terminal portion of the curve, the negative of
which would be the smaller of the two rate constants, K small , (either the summation of all the
ways that the drug is eliminated, K , or the summation of all the ways that the metabolite is
eliminated, K1 ).
• Subtracting the two previous equations yields
km X 0 –( Kbig ⋅ t )
C pm – C pm = 
 
 e
K l arg e – K small Vdm (EQ 416)
which is a straight line on semilog paper with a slope of kbig and an intercept of
km X0
I =   . Note: we can get the larger of the two rate constants from this
K l arg e – K small V dm
method.
TABLE 46
Drug Metabolite
Cp
Time (hr) (mcg/L) Cpm1 (mcg/L) Cpm Cpm – Cpm
0 0 181.2 181.2
0.5 24.7 175 150.3
1 44.4 168.9 124.5
2 139 71.8 157.5 85.7
4 65.6 96.5 136.9 40.4
6 31.1 100 119 19
8 14.6 94.7
12 76.5
24 34
In the above data Cp vs. Time is the plasma profile of the drug from Table 41 on page 2 and
Cpm1 vs. Time is the plasma profile of the metabolite. A plot of Cp vs. Time yielded a straight
0.693 –1
line with a slope,(K) of 0.375 hr1, K =  = 0.375 hr and and intercept of 295 mic/
–1
1.85 hr
L,
10 3
Concentration (mic/L)
100
10 2
Concentration (ng/mL)
50
1.85 hr
10 1
0 2 4 6 8
Time (hours)
Time (hr)
while a plot of Cpm1 vs. Time( Figure 43 on page 54) yields a biexponential plot with a termi
nal slope of 0.07 hr1 , k small = 0.693
 and extrapolating the terminal line back to time = 0
10 hr
yields 181 mic/L.
FIGURE 43. Nifedipine Metabolite (column 3 vs. 1 in Table 46 on page 53)
)
mic
Cpm0 = 181 
L
Concentration (mic/L)
80
102
40
10 hr
101
0 4 8 12 16 20 24
Time (hours)
• You should be able to feather (curve strip) the other rate constant out of the data by plotting the
difference between the extrapolated (to t = 0 ) terminal line (column 4 vs. 1 in Table 46 on
page 53) and the observed data (at early times) (column 3 vs. 1 in Table 46 on page 53) yield
ing a straight line with the slope of the line equal to the negative of the other (larger) rate con
stant (column 5 vs. 1 in Table 46 on page 53).
First you would fill in the Cpm column (column 4 in Table 46 on page 53) by computing Cpm
– k small t
for various values of time i.e Cpm = Cpm 0 ⋅ e where – k small is the terminal slope of the
graph. Then Cpm – Cpm (column 5 in Table 46 on page 53) would be column 4  column 3.
Then a plot of Cpm – Cpm vs. time (column 5 vs. 1 in Table 46 on page 53) is shown below.
10
3
Intercept
2
Column 5
100
102
50 1.85 hr
Half life
1
10
0 1 2 3 4 5 6
Time (hr)
In this case, the slope of the stripped line line is 0.375 hr1 and the intercept is 0.181.2 mic/L.
The slope of 0.375 hr1 should not be surprising as the plot of the data in Figure 43 on page 54
resulted in a terminal slope of .07 hr1 . Since the data set yielded a biexponential plot, sepa
rating out the exponents could only yield K (0.375 hr1) or K1 as determined by our Laplace
Transform information. Thus, the terminal slope could be either K1 or K. Since it was obvi
ously not K, it had to be K1. Thus the other rate constant obtained by stripping has to be K.
You can determine which slope is which rate constant if you have any data regarding intact drug
(i e. either plasma or urine time profiles of intact drug) as the slope of any of those profiles is
always –K .
• You should be able to determine V dm if you have any urine data regarding intact drug (i.e.
urine time profiles of intact drug) as the intercept of those profiles allow for the solution of k m .
Thus the intercept, I, of the extrapolated line of equation 414 could be rearranged to contain
–1 1000 mic
km ⋅ X0 0.375hr ⋅ 25mg ⋅ 
mg
only one unknown variable, V dm =  =  = 170 L .
( K l arg e – K small ) ⋅ I –1 mic
( 0.375 – 0.07 ) hr ⋅ 181.2 
L
Utilization: • You should be able to determine the rate constants using MRT calculations.
MRT Calculations In a caternary chain, each compartment contributes its MRT to the overall MRT of the drug,
thus:
K
X
MRT(IV) = 1/K
Suppose the drug were given by IV bolus. Then the drug would have to be metabolized and the
metabolite eliminated. Since the MRTs are additive, the overall MRT of the metabolite would
be made up of the MRTs of the two processes, thus:
km kmu
X Xm
MRT(met) = MRT(elim)+MRT(IV)
MRT(met) = 1/K1 + 1/K
Thus, using the data from Table 43 on page 5 the MRT(IV)Trap is
 = 1986.1
MRT = AUMC  = 2.42 hr or about MRT = AUMC
 = 2100
 = 2.67 hr using calculus.
AUC 819.9 AUC 787
And using the data from columns 1 and 3 from Table 46 on page 53 the MRT(met) using calcu
 = 36000
lus is MRT = AUMC  = 17 hr.
AUC 2116
4.2.2 URINE
Valid equations:
By this time, it should be apparent that data which fits the same shape curve
(monoexponential, biexponential, etc.) are treated the same way. When the
curves are evaluated, the slopes and intercepts are obtained in the same manner.
The only difference is what those slopes and intercepts represent. These represen
tations come from the equations which come from the LaPlace Transforms which
come from our picture of the pharmacokinetic description of the drug. Please
refer back to the section on graphical analysis in the Chapter 1, Math review for a
interpretation of slopes and intercepts of the various graphs.
Temporarily, please refer to exam section 1, chapter 14 for problems for this sec
tion (until problems can be generated) as well as additional problems for the previ
ous sections.
OBJECTIVES
1. Given patient drug concentration and/or amount vs. time profiles, the student will
calculate (III) the relevant pharmacokinetic parameters available ( V d , K, k m , k r ,
AUC , Clearance, MRT) from IV infusion data.
2. I.V. Infusion dosing for parent compounds
3. Plasma concentration vs. time profile analysis
4. Rate vs. time profile analysis
5. Professional communication of IV Infusion information
6. Computer aided instruction and simulation
7. Metabolite (active vs. inactive)
5.1.1 PLASMA
Valid equations:
Q – Kt
C p =  ( 1 – e ) or (EQ 51)
K ⋅ Vd
Dose – Kt
( 1 – e )
C p =  (EQ 52)
K ⋅ Vd ⋅ T infusion
at any time during the infusion
Q
( C p )ss =  (EQ 53)
K ⋅ Vd
at steady state (t is long)
– Kt
C p = C p( term ) ⋅ e (EQ 54)
Dose is the infusion rate shown in equation 51 and equation 52.
Q = 
T infusion
Q – Kt infusion
C p( term ) =  ( 1 – e ) is the plasma concentration when the
K ⋅ Vd
infusion is stopped.
Rewriting equation 54 to an equation which may be used by a computer results in:
Q  ( e – K ⋅ T∗ – e – K ⋅ T )
Cp =  (EQ 55)
K⋅V
Using The Scientist@‘s Unit function makes the change in T∗ straight forward. In
The Scientist@, Unit(+) = 1 and Unit() = 0, so defining T∗ = ( T – T iv ) ⋅ UNIT ( T – Ti v )
meets these needs.
Utilization: You should be able to determine the infusion rate necessary to obtain a desired
plasma concentration. Rearranging equation 53 results in:
You should be able to determine how long it would take to get to a desired plasma
concentration. Using equation 51 and equation 53, it looks like it will take for
ever to get exactly to steady state because in order for
Q = 
Q ( 1 – e – Kt ) , e – Kt → 0 which occurs when t = ∞ . So,
( C p )ss = 
K ⋅ Vd K ⋅ Vd
how close is close enough? If ( C p ) = 0.95 ⋅ ( C p )ss , that’s good enough in most
people’s estimation. So in order to find out how long it will take we use equation
51, setting ( C p ) = 0.95 ⋅ ( C p )ss and solve for time. Thus:
Q ( 1 – e – Kt ) which results in
( C p ) = 0.95 ⋅ ( C p )ss = 
K ⋅ Vd
– Kt
0.95 = ( 1 – e )
– Kt
0.95 – 1 = – e
ln ( 0.05 ) = – Kt
– 2.996 = – Kt
–
2.996 = t
–K
2.996
t 1 = 4.32t 1 = t , (EQ 57)
0.693 2 2
or about 4.32 half lives to get to 95% of steady state. Generalizing, then, the num
ber of halflives it takes to get to steadystate is equal to the logarithm of the
inverse of how close is close (in this case, 5% or 0.05 = 20) devided by the loga
rithm of two.
Changing infusion rates: Occasionally, it is necessary to change infusion rates to stabilize the patient. If a
patient were started on an infusion rate, Q1, and then at some subsequent time,
T>T*, the infusion rate was changed to Q2, the equation for the concentration after
the change would be:
Q1 – ( K ⋅ T∗ ) – ( k ⋅ ( T – T∗ ) ) Q2  ⋅ ( 1 – e – ( k ⋅ ( T – T∗ ) ) )
Cp =  ⋅ ( 1 – e )⋅e +  (EQ 58)
K⋅V K⋅V
Assuming equilibrium was reached at infusion rate Q1, we could simplify equation
58 by setting T = 0 at the time of the rate change (thus we would be interested in
the time after the change) resulting in:
Q1 –k ⋅ T Q2 –k ⋅ T
⋅e
Cp =  +  ⋅ ( 1 – e ) (EQ 59)
K⋅V K⋅V
Under these conditions, it would be useful to determine the time to reach the new
equilibrium. As before, within 5% is close enough. Thus if we are coming down
Q2 and if we were
(lowering the Cp, i.e. Q2 < Q1), we would want Cp = 1.05 
K⋅V
Q2 . Taking
going up (raising the Cp, i.e. Q2 > Q1), we would want Cp = 0.95 

K⋅V
the first condition we find:
Q2 Q1 –k ⋅ T Q2  ⋅ ( 1 – e – k ⋅ T )
Cp = 1.05  =  ⋅ e +  (EQ 510)
K⋅V K⋅V K⋅V
⋅ Q2
ln 0.05

Q1 – Q2
T =  (EQ 511)
–K
0.05 ⋅ Q2
ln –
Q1 – Q2
T =  (EQ 512)
–K
Combining equation 511 and equation 512 and rearranging results in:
ln 
Q1 – Q2 ⋅ 20 ln  Q1 – Q2 ⋅ 20
Q2 Q2
T =  =  ⋅ t 1 ⁄ 2 (EQ 513)
K 0.693
Thus it is the absolute value of the difference of the two rates and the elimination
rate constant which determine the length of time needed to establish a new equilib
rium. Under the conditions of Q1 = 0 , that is no previous infusion, and the dif
ference is maximal equation 513 simplifies to equation 57. Under the conditions
of Q1 = Q2 , the equation is undifined and has no utility (as well as makes no
sense, because the equation was designed to be used when there was a change in
rate.) However, lim T = 0 , thus no change results in zero time to get to the new
Q2 → Q1
equilibium. Similar to equation 57 as before, the generalization for the number of
halflives it takes to obtain the new steadystate is the logarithm of (the fractional
difference of the rates (or the steadystate concentrations) times the inverse of how
close is close) devided by the logarithm of two.
As pharmacokinetic equations are additive, you should be able to determine a
loading dose (by I.V. bolus, for example) and a maintenance dose (infusion rate)
for a patient to extablish an equilibrium. If, for example, you want to give a load
ing dose followed by an IV infusion, the generalization for the number of half
lives it takes to obtain the new steadystate is the logarithm of (the fractional dif
ference of the concentrations, Cp0 and Cpss, times the inverse of how close is
close) devided by the logarithm of two.
Discussion: IV infusion is a controlled way to get drug into your patient. Using patient popula
tion average pharmacokinetic parameters (K, Vd) available in the drug mono
graphs, you are able to make a professional judgement about:
1. the plasma concentration that you would like to achieve (from therapeutic range) and the time in
which you would like to get there.
2. the infusion rate necessary to get to the target concentration, and
3. the time necessary to to get there.
Using population average parameters for K and Vd, equation 56 results in:
53.2 mg
 ⋅ 8 hr = 425 mg of theophylline.
hr
How long to get to steady After setting up the infusion, the doctor asks, “How long to steady state?
state?
Using equation 57, our patient who has an eight hour half life, will take about
4.32 ⋅ 8 hr = 34.6 hr to get to 95% of steady state. The patient doesn’t want
relief in a day and a half. He needs to breathe NOW. What would you suggest?
Infusion takes too long. It might be possible to give him an IV Bolus dose stat which would get him to
How do we get relief Dose
now? IV Bolus stat. ( C p )ss right away. This is done by converting ( C p )ss =  to
Vd
V d ⋅ ( C p ) ss = Dose .
Q 2Q – Kt – Kt
( C p )ss =  =  ( 1 – e ) which yields 1 = 2 ( 1 – e ) and so
K ⋅ Vd K ⋅ Vd
1 – Kt 1 – Kt
 = 1 – e . Thus  – 1 = – e . Taking the ln of both sides ln ( 0.5 ) = –Kt
2 2
ln ( 0.5 ) = 0.693
  t 1 = t 1 = t or that it will take one halflife to get to the target
–K 0.693 2 2
plasma concentration (which is the Cpss obtained by the infusion rate of 1Q) if you
run the infusion at a faster rate, 2Q. So for your patient, you might suggest an
infusion of 1000 mg over 8 hours (2Q for one half life) to get to steady state
quickly and then back off to 500 mg over 8 hours for the second 8 hours.
Q
( C p )ss =  (EQ 514)
Cl
How do we calculate and equation 514 can be rewritten to:
Clearance from IV infu
sion data? Q 
Cl =  (EQ 515)
( C p )ss
Thus, assuming steady state, the clearance can be calculated by dividing the infu
sion rate by the resultant steady state plasma concentration.
How do we separate K Graphing equation 54 which relates the decline in plasma concentration after ces
and Vd out of Clear sation of the infusion, the resultant slope of the line yields  K, the elimination rate
ance? constant. Dividing the elimination rate constant,  K, obtained by equation 54 into
the clearance obtained by equation 515 results in the other necessary pharmacoki
netic parameter, Vd.
How can we utilize the From our original model
rate of change of
plasma concentration to d
determine the pharma X = Q – (K ⋅ X ) (EQ 516)
dt
cokinetic parameters, K
and Vd?
X . Thus , V ⋅ C p = X . Rewriting equation 516 yields:
and Cp =  d
Vd
dC p Q e – Kt
=  (EQ 517)
dt Vd
vs. t ( actually, ∇
dCp Cp
Thus a plot of  vs. tmid exactly like we did in urinary
dt ∇t
rate graphs) of the ascending portion of the plasma profile would result in a
straight line with a slope of K and an intercept of  Q .
Vd
5.2 Problems
Equations needed for solving the problems:
1. k from the slope of the terminal portion of the graph of Cp vs. T
0.693
2. t 1 ⁄ 2 = 

k
3.
Q
Volume of distribution from Cp =  ( 1 – e
– Kt
)
K ⋅ Vd
4. Clearance Cl = K ⋅ V d
Cpss. Q = Cp ss ⋅ K ⋅ V d
Dose loading = Cp ss ⋅ V d
c. How long will it take to reach steady state?
T 95 = 4.32 ⋅ T 1 ⁄ 2
d. Find the plasma concentration if the infusion is discontinued at time = Tdc hours.
Q ( 1 – e – ( K ⋅ Tdc ) ) .
Cp dc = 
K ⋅ Vd
e. Find the plasma concentration Tpost hours after infusion is discontinued at time = Tdc hours.
– ( K ⋅ T post )
Cp post = Cp dc ⋅ e
Acyclovir (Problem 5  1)
Acyclovir (225.21 g/Mole) is an antiviral drug used in the treatment of herpes simplex, varicella zoster, and in suppres
sive therapy. In this study, patients were given varying doses of acyclovir over one hour by infusion. Acyclovir distrib
utes uniformly into the plasma and tissues such that the plasma concentration is representative of tissue concentration.
Acyclovir is 30% metabolized and 70% renally excreted. The following data was obtained from an intravenous infu
sion dose of 2.5 mg/kg over one hour where the patient weighed 70 kg.
PROBLEM TABLE 5  1. Acyclovir
umol 
Plasma concentration

L
Time (hours)
0 0
0.25 7
0.5 12
0.75 17
1 20
2 10
3 5
5 1
2. t1 ⁄ 2
3. Volume of distribution
4. Clearance
“Acyclovir” on page 11
102
Concentration
101
100
0 1 2 3 4 5
Time
a. Calculate the infusion rate necessary to maintain a plasma concentration of 25 umol ⁄ L = 111 mg/hr
b. Suggest a loading dose for the patient which would give you Cpss immediately. 148 mg
c. How long will it take to reach steady state? 4 hr
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours. = 25 umol ⁄ L
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours. = 5.6 umol ⁄ L
Aminophylline (Problem 5  2)
Aminophylline is used in the treatment of bronchospasm. In this study, aminophylline was given by intravenous infu
sion to patients with a mean weight of 75.7 kg. The doses given were chosen to maintain a between 10 20 mg/L based
on desirable body weight. The doses were given at a rate of 0.5 mg/kg/hour (Theophylline) for 84 hr. The following
set of data was collected.
PROBLEM TABLE 5  2. Aminophylline
mg
Plasma concentration

L
Time (hours)
0 0.
6 5
12 8
24 11
30 11.6
36 12.0
48 12.4
54 12.5
66 12.6
72 12.8
84 12.8
88 9
92 6.4
96 4.6
100 3.2
1. k 2. t1 ⁄ 2
3. Volume of distribution 4. Clearance
5. 6. You wish to maintain a plasma concentration of 15 mg/L in your patient.
a. Calculate the infusion rate necessary to maintain a plasma concentration of 15 mg/L.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours.
“Aminophylline” on page 13
102
CONCENTRATION
101
0
10
0 20 40 60 80 100
Time
1. k = 0.085 hr1
2. t 1 ⁄ 2 = 8.15 hr
3. Vd = 35.3 L
4. Cl = 3 L/hr
5a. Q = 45 mg/hr
5b. D L = 530 mg
ss
5c. t = 35 hr
95%
5d. C p = 5.2 mg/L
Carmustine (Problem 5  3)
mg
Plasma concentration 
Time (minutes) L
15 .3
30 .5
60 .7
90 .75
120 .8
135 .5
142.5 .4
150 .3
2. t1 ⁄ 2
3. Vd
4 Cl
2
5. A patient with a BSA of1.8 M is to be given BCNU by IV infusion. You wish to maintain a plasma
“Carmustine” on page 15
0
10
CONCENTRATION
1
10
0 50 100 150
TIME
1. k = 0.031 min1
2. t 1 ⁄ 2 = 22 min
3. Vd = 198 L/M2
4 Cl = 6.15 L/M2/hr
2
5. A patient with a BSA of1.8 M is to be given BCNU by IV infusion. You wish to maintain a plasma
b. Suggest a loading dose for the patient which would give you Cpss immediately.
Dose = Cp ss ⋅ Vd = 2µmole 214µg ⋅ 
mg  ⋅ 
198L ⋅ 1.8M 2 = 150mg
 ⋅ 
L µmole 1000µg M 2
c. How long will it take to reach steady state? 4.32 * T 1/2 = 97 min.
d. Find the plasma concentration if the infusion is discontinued at time = 10 min. = 0.1197 mg/L
e. Find the plasma concentration 1 hour after infusion is discontinued at time = 10 min. = 0.017 mg/L
Cefotaxime (Problem 5  4)
Cefotaxime is a third generation cephalosporin which is widely used as an antimicrobial in neonates, infants, and chil
dren. In this study, infants and children were given a 50 mg/kg dose of cefotaxime intravenously over 0.25 hour. The
following data was collected:
PROBLEM TABLE 5  4. Cefotaxime
mg
Plasma concentration

L
Time (hours)
0.00 0
0.05 35
0.10 70
0.20 140
0.35 155
0.60 130
0.85 110
1.20 80
1.30 75
2.00 45
2.40 35
3.40 15
4.50 8
6.50 1.7
From this data, assuming that the patient weighs 30 kg, determine the following:
1. k
2. t1 ⁄ 2
3. Vd
4. Cl
5. You wish to maintain a plasma concentration of 80 mg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 80mg/L
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 0.25 hours.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 0.25 hours.
“Cefotaxime” on page 17
103
CONCENTRATION
102
101
100
0 1 2 3 4 5 6 7
TIME
1. k = 0.733 hr1
2. t 1 ⁄ 2 = 0.945 hr
3. Vd = 0.276 L/kg
4. Cl = 0.202 L/kg/hr
ss
4c. t = 4.1 hr
95%
4d. C p = 13.35 mg/L
Ganciclovir (Problem 5  5)
Ganciclovir is used against the human herpes viruses, cytomegalovirus retinitis, and cytomegalovirus infections of the
gastrointestinal tract. In this study, twentyseven newborns with cytomegalovirus disease were given 4 mg/kg of ganci
clovir intravenously over one hour. Blood samples were taken and the data obtained is summarized in the following
table:
PROBLEM TABLE 5  5. Ganciclovir
2. t1 ⁄ 2
3. Vd
4. Cl
4. A patient is to be given ganciclovir by IV infusion to an infant weighing 6.1 kg. You wish
to maintain a plasma concentration of 5.5 mcg/mL. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 5.5mcg/mL.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 1 hour.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 1 hour.
“Ganciclovir” on page 19
10 1
CONCENTRATION
10 0
101
0 2 4 6 8
Time
1. k = 0.255 hr1
2. t 1 ⁄ 2 = 2.72 hr
3. Vd = 0.687 L/kg
4. Cl = 0.175 L/kg/hr
1000ml ⋅ 0.687L
Q = Cp ss ⋅ V d ⋅ K = 5.5µg  ⋅ 6.1kg ⋅ 0.255
mg  ⋅ 
 ⋅   = 5.9mg

5a. 
ml 1000µg L kg hr hr
1000ml ⋅ 0.687L
D L = Cp ss ⋅ Vd = 5.5µg  ⋅ 6.1kg = 23mg
mg  ⋅ 
5b.  ⋅ 
ml 1000µg L kg
ss
5c. T = 4.32 ⋅ t1 ⁄ 2 = 11.75hr
95%
5.9mg

Q hr – K ⋅ 1hr
) = 1.24mg
– Kt
5d. C p term =  ( 1 – e ) = 
 (1 – e 
K ⋅ Vd 0.255
 ⋅ 0.687L L
 ⋅ 6.1kg
hr kg
– K ⋅ 2hr
5e. C p = C p term ⋅ e = 1.24mg
 ⋅ 0.6 = 0.74mg

L L
Gentamicin (Problem 5  6)
Gentamicin is an aminoglycoside antibiotic which is frequently used in the treatment of gramnegative bacilli infec
tions. Since it has a low therapeutic index, it is important to determine proper dosage regimens. In this study, patients
on peritoneal dialysis received a 30 minute intravenous infusion of 80 mg gentamicin in 100 mL of 5% dextrose in
water. The following data was collected:
PROBLEM TABLE 5  6. Gentamicin

ug
Plasma concentration
mL
Time (hours)
0.50 5.68
1.50 5.15
3.70 4.80
7.35 3.99
11.30 3.35
24.00 2.02
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given gentamicin by IV infusion. You wish to maintain a plasma concentration
of 5.2 ug ⁄ mL . Determine the following:
“Gentamicin” on page 21
101
CONCENTRATION
100
0 5 10 15 20 25
Time
1. k = 0.0431 hr1
2. t 1 ⁄ 2 = 16.1 hr
3. V d = 14.5 L
4. Cl =0.625 L/hr
ss
5c. t = 69.6 hr
95%
5d. C p = 0.11 mg/L
HA1A is an immunoglobulin antibody. In this study, patients received a 250 mg intravenous infusion of HA1A over
15 minutes. Serum levels were measured before and after infusion and the following data was collected:
PROBLEM TABLE 5  7. Human Monoclonal Antilipid A antibody (HA1A)
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given HA1A by IV infusion. You wish to maintain a plasma concentration of 100 µg/mL.
Determine the following:
101
0 20 40 60 80
Time
1. k = 0.0282 hr1
2. t 1 ⁄ 2 = 24.4 hr
3. V d = 3.2 L
4. Cl = 0.09 L/hr
5a. Q = 9 mg/hr
5b. D L = 320 mg
ss
5c. t = 105 hr
95%
5d. C p = 2.78 mg/L
Ifosfamide (Problem 5  8)
Ifosfamide is an agent which has shown some pharmacological response in the treatment of cancer. In this study, a 5
2 2
g⁄m dose of ifosfamide was infused over 30 minutes. The median BSA for the subjects was 1.8 m . The
following data was obtained:
PROBLEM TABLE 5  8. Ifosfamide

ug
Plasma concentration
mL
Time (hours)
0 0.0
0.5 285.0
1 260.0
2 220.0
4 160.0
6 112.0
8 80.0
10 60.0
24 5
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given ifosfamide by IV infusion. The patient has a BSA 1.8 M2. You wish to maintain a
plasma concentration of 336 µg/mL. Determine the following:
“Ifosfamide” on page 25
103
102
CONCENTRATION
101
100
0 5 10 15 20 25
Time
1. k = 0.1716 hr1
2. t 1 ⁄ 2 = 4.04 hr
3. V d = 16.6 L/M2
4. Cl = 2.85 L/hr/M2
5a. Q = 1.725 g/hr
5b. D L = 10 g
ss
5c. t = 17.5
95%
5d. C p = 18.7 mg/L
Isosorbide 5mononitrate (5ISMN) is a metabolite of isosorbide dinitrate. In this study, the kinetics of isosorbide 5
mononitrate were looked at in 12 healthy patients after an intravenous infusion of 20 mg at 8 mg/hour for 2.5 hours.
This drug follows onecompartment, open model kinetics. The following data was collected:
PROBLEM TABLE 5  9. Isosorbide 5mononitrate
102
101
100
0 5 10 15 20 25 30
Time
1. k = 0.168 hr1
2. t 1 ⁄ 2 = 4.125 hr
3. V d = 44.6 L
4. Cl = 7.5 L/hr
5a. Q = 2.25 mg/hr
5b. D L = 13.4 mg
ss
5c. t = 17.8 hr
95%
5d. C p = 46.4 ng/mL
Moclobemide is reversibly inhibits the Aisozyme of the monoamine oxidase enzyme system. In this study, twelve
patients received a 96.7 mg dose as an intravenous infusion over 20 minutes. Blood samples were obtained during the
infusion and after the infusion was ended and the following data was obtained:
PROBLEM TABLE 5  10. Moclobemide
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given moclobemide by IV infusion. You wish to maintain a plasma concentration
of 1mg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 1mg/L.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 15 min.
e. Find the plasma concentration 3 hours after infusion is discontinued at time = 15 mins.
“Moclobemide” on page 29
10 0
CONCENTRATION
101
102
0 1 2 3 4 5 6 7
Time
1. k = 0.44 hr1
2. t 1 ⁄ 2 = 1.6 hr.
3. V d = 90.4 L
4. Cl = 39.8 L/hr
5a. Q = 40 mg/hr
5b. D L = 90 mg
ss
5c. t = 6.8 hr
95%
5d. C p = 0.1 mg/L
Obidoxime is an agent which is used as an antidote in organophosphate poisoning. In this study, the pharmacokinetics
of obidoxime were studied in a 20 year old patient who attempted to commit suicide by ingesting Tamaron (60% meth
amidophos, an organophosphate, in ethylene glycol monethyl ether). She was given 4 mg/kg Obidoxime by intrave
nous infusion over 10 minutes and the following data was collected:
PROBLEM TABLE 5  11. Obidoxime
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given obidoxime by IV infusion. The patient has a body weight of 60 kg.
You wish to maintain a plasma concentration of 10 µg/mL. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 10 ug ⁄ mL .
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 30 minutes.
e. Find the plasma concentration 1 hour after infusion is discontinued at time = 30 minutes.
“Obidoxime” on page 31
102
CONCENTRATION
101
100
0 50 100 150 200 250 300
Time
1. k = 0.00463 min1
2. t 1 ⁄ 2 = 150 min
3. V d = 0.22L/kg
4. Cl = 1 mL/min
5a. Q = 0.61 mg/min
5b. D L = 132 mg
ss
5c. t = 10.8 hr
95%
5d. C p = 1.3 mg/L
Perindoprilat and other ACE inhibitors are used in the management of hypertension and chronic congestive heart fail
ure. In this study, a 1 mg dose was infused over a one hour period. The following data was collected:
PROBLEM TABLE 5  12. Perindoprilat
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given perindoprilat by IV infusion. You wish to maintain a plasma concentration
of 30 ng/ml. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 30 ng/mL.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours.
“Perindoprilat” on page 33
102
CONCENTRATION
101
100
0 20 40 60 80 100 120
Time
1. k = 0.0087 min1
2. t 1 ⁄ 2 = 79.6 min
3. V d = 18.9 L
4. Cl =164 mL/min
5a. Q = 5 µg/min
5b. D L = 0.57 mg
ss
5c. t = 5.73 hr
95%
5d. C p = 27.8 ng/mL
This study looks at the affinity of sulfonamides for carbonic anhydrase. Doses of 8 micromoles/kg were administered
via the jugular vein cannula in approximately 0.5 mL of PEG 400 over 5 minutes at a constant rate. Samples were col
lected during the infusion period and for 30 minutes afterward. The following set of data was collected:
PROBLEM TABLE 5  13. Sulfonamides
2. t1 ⁄ 2
3. Vd
4. Cl
5. A 70kg patient is to be given a sulfonamide by IV infusion. You wish to maintain a plasma
concentration of 30 µM. Determine the following:
a. Calculate the infusion rate which would be necessary to maintain the plasma concentra
tion of 30 µM.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 4 hours.
e. Find the plasma concentration 30 minutes after stopping infusion at time = 4 hours.
“Sulfonamides” on page 35
102
CONCENTRATION
101
100
0 5 10 15 20 25 30 35
Time
1. k = 0.0705 min1
2. t 1 ⁄ 2 = 9.8 min
3. V d = 0.18 L/kg
4. Cl = 12.7 mL/min/kg
5a. Q = 26.9 µmole/min
5b. D L = 380 µmole
ss
5c. t = 42 min
95%
5d. C p = 30 µmole/L
Terodiline is an agent which works as an anticholinergic and a calcium antagonist. It is used to treat incontinence. It
is metabolized into pHydroxyterodiline, which is further metabolized to 3,4dihydroxyterodiline. The parent drug and
all of its metabolites are excreted into the urine as well as the feces. A patient is given 12.5 mg of Terodiline by IV
infusion at a rate of 1 mL/ minute for 5 minutes. The following data is collected:
PROBLEM TABLE 5  14. Terodiline
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given terodiline by IV infusion. You wish to maintain a plasma concentration
of 40 mcg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain the plasma concentration of40 mcg/L.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours.
e. Find the plasma concentration 2 hours after stopping infusion if the infusion ended at
time = 5 hours.
“Terodiline” on page 37
102
CONCENTRATION
101
100
0 50 100 150 200 250
Time
1. k = 0.0136 hr1
2. t 1 ⁄ 2 = 50.9 hr
3. V d = 283 L
4. Cl =3.85 L/hr
5a. Q = 0.154 mg / hr
5b. D L = 11.32 mg
ss
5c. t = 220 hr
95%
5d. C p = 2.63 µg/L
Tinidazole is an antimicrobial similar to metronidazole which is used in the treatment of trichomoniasis, giardiasis,
amoebiasis, and anaerobic infections. This study focuses on the pharmacokinetics of tinidazole in patients suffering
from severe renal failure. Twelve patients received 800 mg of tinidazole dissolved in 400 mL of dextrose monohydrate
solution as an intravenous infusion at a rate of 60 mg/min. Blood samples were taken and the following data was
obtained:
PROBLEM TABLE 5  15. Tinidazole
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given tinidazole by IV infusion. Determine the following:
a. Calculate the infusion rate necessary to maintain the plasma concentration of 25 mg/L.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 1 hour.
e. Find the plasma concentration 2 hours after stopping infusion if the infusion was stopped
at time = 1 hour.
“Tinidazole” on page 39
102
CONCENTRATION
101
100
0 10 20 30 40 50
Time
1. k = 0.04136 hr1
2. t 1 ⁄ 2 = 16.75 hr
3. V d = 54.7 L
4. Cl = 2.26 L/hr
5a. Q = 56.6 mg/hr
5b. D L = 1.37 g
ss
5c. t = 72.4 hr
95%
5d. C p = 1 mg/L
Most persons with cystic fibrosis (CF) become colonized with Pseudomonas aeruginosa in their bronchial secretions
within their second decade of life. These patients require frequent treatment with potent antipseudomonal antibiotics
such as Tobramycin. In this study, an intravenous infusion of 2.5 mg/kg tobramycin was given over 35 minutes. The
following data was collected:
PROBLEM TABLE 5  16. Tobramycin
mg

L
Plasma concentration
Time (minutes)
35 8.00
60 6.00
90 4.50
150 2.50
270 0.75
2. t1 ⁄ 2
3. Vd
4. Cl
5. A patient is to be given tobramycin by IV infusion. The patient has a body weight of 70 kg. You wish
to maintain a plasma concentration of 10 mg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain the plasma concentration of 10 mg/mL.
b. Suggest a loading dose for the patient which would give you Cpss immediately.
c. How long will it take to reach steady state?
d. Find the plasma concentration if the infusion is discontinued at time = 30 minutes.
e. Find the plasma concentration 1 hour after stopping infusion if the infusion wasstopped at
time = 30 minutes.
“Tobramycin” on page 41
101
CONCENTRATION
100
101
0 50 100 150 200 250 300
Time
1. k = 0.01 min1
2. t 1 ⁄ 2 = 69.3 min
3. V d = 0.269 L/kg
4. Cl = 2.7 mL/min
5a. Q = 0.027mg/kg/min = 1.62 mg/kg/hr
5b. D L = 2.7 mg/kg
ss
5c. t = 300 min = 5 hr
95%
5d. C p = 2.6 mg/L
OBJECTIVES
After successfully completing this chapter, the student shall understand:
1. Physiology and machanisms of absorbtion
2. Effects of diffusion, cardiac output / blood perfusion, physical properties of the
drug and body on distribution
3. Biotransformation, first pass effect, and clearance
4. Renal, biliary, mammary, salivary, other forms of excretion.
5. identify the effects of physiological changes with age, sex, and disease on the
absorption, distribution, metabolism, and excretion of a drug.
OBJECTIVES
After successfully completing this chapter, the student shall be able to
1. Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the relevant pharmacokinetic parameters ( V d , K, k m , k r , k a , AUC ,
Clearance, MRT, MAT) available from oral data.
2. Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the K from the terminal portion of the curve.
3. Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the k a from either the curve stripping Moment techniques.
4. Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the Absolute Bioavailability from comparing IV and oral (or
some other process which involves absorption) data.
5. Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the Comparative Bioavailability from comparing the generic to the
inovator product.
6. Given patient drug concentration and/or amount vs. Time profiles, the student will
qualitatively evaluate (IV) bioequivalence as determined by rate of absorption
(peak time) and extent of absorption (Area Under the Curve  AUC, and ( Cp ) max ).
7. Given patient drug concentration and/or amount vs. Time profiles, the student will
evaluate (IV) bioequivalence data.
8. Given patient drug concentration and/or amount vs. Time profiles, the student will
lucidly discuss (IV) bioequivalence and recommend (V) to another competant
professional if s/he believes products to be equivalent.
ka –k t
C p = fD
– Kt
 ⋅ 
 ⋅ (e – e a ) (EQ 518)
Vd k a – K
ln ( k a ⁄ K )
t p =  (EQ 521)
( ka – K )
X
a = K ⋅ AUC ∞ – ( C p + K ⋅ AUC t ) (EQ 522)
v
f = the absolute bioavailabilty; the fraction of dose which ultimately reaches sys
temic circulation (which is made up of the fraction of the dose which is absorbed
times the fraction which gets past the liver (first pass effect))
7.1.2 UTILIZATION
The following information is available for ampicillin: 90% is excreted unchanged and a 250 mg IV bolus dose yields an
AUC of 11 mic/mL*hr. The following blood level profile has been reported for two brands of ampicillin which were
given as 500 mg oral capsules.
TABLE 47
µg
MEAN SERUM LEVEL 
Time (hr) mL
LEDERLE BRISTOL
0.5 0.37 0.38
1.0 1.97 1.91
1.5 2.83 2.49
2.0 3.15 3.11
3.0 2.73 2.79
4.0 1.86 1.95
6.0 0.43 0.49
g. Cl
h. Vd
j. Cp max
The data was plotted as above with the best fit line drawn. From the graph the fol
lowing parameters were derived:
A B
1 70.0 77.1
2 79.5 82.3
3 80.7 69.4
4 68.6 60.6
6 49.4 48.0
8 35.0 33.7
12 15.3 17.4
24 2.1 3.0
Calculate peak time and Cp max and AUC for both products.
Answer:
A B C D
1 1.79 6 0.45
2 1.36 12 0.08
4 0.78
Why/Why not?
g} How long would it take that infusion rate to attain a therapeutic plasma con
centration of 0.5 mic/ml ?
Answer:
IV Bolus Parameters:
Cp max2.4 mic/mL
AUC 8.5
K 0.283 hr^1
5/2/8.5 = 0.61
Very well. Only 61% (f) of liquid gets in and you would expect only 77% of that to
show up in the urine because only 77% of the IV dose shows up in the urine
(.61*.77=.47).
f} How long would it take that infusion to attain a therapeutic plasma concentra
tion of 0.5 mic/ml ?
a) Find ka
5.5 33 1.5 65
4.1 40 1.1 80
2.9 52
If 100 mic dose were given by IV bolus, how long would it be before the volunteer
would regain 80% of his control?
Answwer:
T max 1.7 hr
AUC (trap)30.07
K 0.225 hr^1
Ka 1.22 hr^1
f (AUCoral/Doseoral)/(AUCiv/Doseiv) = .98
dR/dln(c) = 27.86
100 mic dose IV yields Cp0 of (Cp0 =AUC * K = 20.4 * 0.225) 4.59ng/mL.
T = 6.76 hours
5. The following data was collected from a double blind cross over study between
500 mg dose of cloxacillin made by Bristol (Tegopen@) and a generic product
which you might want to put in your store.
Answer:
Actual evaluation of ka and peak time is dificult because of the pucity of data at
early time points however all relavent parameters meet guidlines.
g) Tetracycline has a pKa of 9.7. Tetracyclines tend to localize in the dentin and
enamel of developing teeth causing hypoplasia and permanent discoloration of
teeth. Would you recomend tetracyline for a 110 pound lactating mother ?
Support your argument with the dose of the child. (Child's weight 11 lbs. and he
eats 2 oz of milk every 2 hours. Mom's average plasma concentration is main
tained at 3 mic/ml by taking 250 qid. pH of the milk is 6.1, pH of blood is 7.4)
Answer:
Pharmacokinetic parameters:
Lederle Mylan IV
Ratio of bioequivalence parameters (Cpmax, Tmax and AUC) are all within guide
lines. So, the would be considered bioequivalent.
Dose the kid gets is mom's plasma concentration * Ratio(M/b) * volume of milk /
day = 3 mic/mL * 200 * 60cc * 12 feedings = 432 mg.day
Answer:
With only one data point in the early time points, the larger rate constant is in ques
tion. The terminal slope is assumed to be K. The AUC will yield the amount of
ketameperidine which was metabolized (dXmu/dt * t = Xmu).
K (hours^1) 0.216
AUC (mg)30.3
kr = K  km = 0.085 hours^1
Answer:
AUC (mg/L)*hr117.8
K (hr^1) 0.096
ka (hr^1) 2.11
f = (AUCoral/DOSEoral)/(AUCiv/DOSEiv) =
Vd
AUC * K = Cp0iv
Infusion rate = Q = Cpss * TBC = 15 mg/L * 2.83 L/hr = 42.45 mg/hr Theophyl
line = 42.45/.85 = 50 mg/hr Aminophylline
Abbott labs has provided the following data conserning their ORETIC tablets
(hydrochlorthiazide tablets U.S.P.) Dose given was 50 mg.
Answer:
The data is plotted both without (first figure) and with (second figure) a lagtime
which is associated with the release of the drug from the delivery system. Note
that the addition of the lagtime improves the fit.
WithoutWith
1 1.79
2 1.36
4 0.78
6 0.45
12 0.08
a} find K, Cp0.
Both can be found from the graph. K = .283/hr Cp0 = 2.36 mic/ml
5.2/8.5 = 0.61
Very well. Only 61% (f) of liquid gets in and you would expect only 77% of that
to show up in the urine because only 77% of the IV dose shows up in the urine
(0.61 * .77 = .47).
d} How can you explain the variation in % recovered intact in the urine?
g} How long would it take that infusion rate to attain a therapeutic plasma concen
tration of 0.5 mic/ml ?
Roxane labs of Columbus, Ohio offers the following data for your review of their
Quinidine Sulfate tablets (Dose 200 mg). It is compared against the reference
standard by Ely Lilly and company at the same dose.
Roxane Lilly
1 .42 .58
2 .73 .77
3 .71 .74
4 .61 .66
6 .45 .52
8 .32 .34
12 .20 .22
Answers
0.5  50
1  77
1.5  100
2 29 100
3 24 90
4 18 78
5 15 59
6 11 45
7 9 32
a) find ka
c) Calculate TBC
w/o w
a) Calculate TBC
c) Calculate the effect on total body clearance in a patient with viral hepititis (FI =
0.3).
(.517)(18.8) = 9.72
d) Calculate the effect on total body clearance in a patient with stenosis (FR = 0.3).
The patient with viral hepatitis would need modification in therapy. Because
of the decrease in TBC, we can see that the drug is staying the body much
longer than normal, therefore the dosage regimen should be decreased.
(hours) Hygroton@Generic
.5 0.14 0.15
1 0.51 0.64
2 1.23 1.67
3 1.94 2.48
4 2.20 2.91
6 2.64 3.49
8 2.86 3.52
12 3.43 3.82
24 3.22 3.38
48 2.45 2.74
72 1.53 1.91
96 1.20 1.40
Pharmacokinetic parameters
Ka (hr^1)0.168 0.253
Ke (hr^1)0.019 0.019
blood presure
(336/50mg)/(293/50mg) = 1.15
No. The maximum concentration the generic is too much greater than that of
the brand name product.
R(G/H)
AUC (0 to inf)115 ok
Buspirone is a new anxiolytic agent that has been found to be effective for the
treatment of generalized anxiety disorder at a mean dose of approximately 20 mg/
day orally in divided doses. Buspirone is metabolized almost entirely. Less than
0.1% is found intact in the urine. The following data has been presented by Gam
mans (Am J Med:80(supp 3b),4151;1986):
0.25  1.07
2 2.80 2.51
3 2.10 2.05
4 1.57 1.60
6 0.8 0.91
a) find ka
answer:
IV Oral
ka (hr^1) 1.3
= 0.04
Time(Hr.)Formulation BFormulation A
2.0 9.3
2.5 10.3
3.0 10.9
4.0 11.6
6.0 11.4
8.0 10.5
12.0 8.3
18.0 5.7
24.0 3.8
2) Five hundred mg of valproate was administered by IV bolus. The AUC for that
route was 574 mg/L * hr. Calculate f for formulation A. Calculate Cp0 for the IV
dose.
need to respond to another health professional who asked you to stock that formu
lation for his patients.
Answers:
Formulation B R(A/B)
ka = 0.493 hr^1
K = 0.0655
cpmax =
(ka/(kak))*(fX0/Vd)*(exp(k*tmax)exp(ka*tmax)
13.3 mg/L
= (287/250)/(574/500)
= 1.0
The following data was made available by Lederle Labs regarding its generic
Procainamide HCl. (Dose 250mg).
g) Would you recommend your patient breast feed her newborn? Prepare a short
consult for her physician. Support your argument with the dose of the child.
(Child's weight 11 lbs. and he eats 2 oz of milk every 2 hours. Mom's average
plasma concentration is maintained at 4 mic/ml from a 1 g dose ever 6 hours. pH of
the milk is 6.3, pH of blood is 7.4)
j) Calculate the effect on her total body clearance if she were to contract viral hep
atitis which effect liver function (FI = 0.4). Prepare a short consult for her physi
cian as to whether you would recommend a change in therapy. d) Calculate the
effect on her total body clearance stenosis of the liver (FR = 0.4). Prepare a short
consult for her physician as to whether you would recommend a change in therapy.
Answers:
IV LederleSquibb R(L/S)
t lag 0 0 0.24
= 7.4 / 8.57
= 0.86
Echizen and Eichelbaum (Clin Pkin 1986; 11:42549) and Kleinbloesem et al (Clin
Pcol Therap 1986; 40: 218) Reviewed the pharmacokinetics of Nifedipine. While
the drug is not routinely given by IV bolus and does not strictly conform to a one
compartment model, lets treat the data as if those problems can be ignored. The
following data is offered for evaluation:
Formula AFormula B
Time Cp Cp Cp
1 42.1 43.7
3 36.2 25.5
4 65.6 27 20.7
12 1.5 1.0
d} Can you conclude that these products are bioequivalent ? (you must support you
argument)
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