Absorption Model PK Concordia Cayetano c0029 Oct 2017 Pedro Zavala in Class Posting

ABSORPTION MODEL
PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

PEDRO ZAVALA/ABSORPTION-MODEL/OCT 2017 1
SOURCES
Some portions of lecture notes

extracted from SHARGEL & DIPIRO

OBJECTIVES
1. Explain the absorption model
2. Recognize pchem and clinical PK terms in the

absorption model
3. Calculate pchem and clinical PK parameters using

the absorption model

SECTIONS
A. ABSORPTION MODEL
B. EQUATION RECOGNITION EXAMPLE
C. TERMS
D. IN CLASS EXERCISES

A. ABSORPTION MODEL
1 compartment model ; V = volume of distribution (L)

ka = Absorption rate constant (first order, h-1)
k = Elimination rate constant (first order, h-1)

ABSORPTION MODEL

ABSORPTION MODEL
❖ Previous diagram shows absorption phase,
elimination phase, Cmax , tmax
❖ More exact name: 1st Order Absorption,
1st Order Elimination, 1 Compartment Model
❖ Absorption Model Characteristics
❖ One compartment
❖ First order absorption
❖ First order elimination
ABSORPTION MODEL
❖ dC/dt = Rate In – Rate Out

❖ dC/dt = Change in system [drug] per time
❖ Rate In = Drug absorption rate (from GI into system)
❖ Rate Out = Drug elimination rate (from system)

Comment: Model typically used for oral absorption but applies to
other EV routes, e.g., skin patches, suppositories, IM
ABSORPTION MODEL
C = Drug plasma level (mg/L)

V= Volume of distribution (L)
F = Bioavailability ; D = Administered dose (mg)
ka = absorption rate constant (h-1)
k = elimination rate constant (h-1)
ABSORPTION MODEL
Resembles
Where A’ is a constant
Note: A’ is used as a constant, do not confuse with A used for amounts

ABSORPTION MODEL
Model equation can be written in different ways

B. EQUATION RECOGNITION
ABSORPTION MODEL EXAMPLE
ABSORPTION MODEL
EXAMPLE

EQUATION RECOGNITION
Following oral intake of three 500 mg tablets of a
cardiac drug (bioavailability 45%), patient plasma
drug levels (mg/L) vs. time (h) were given by

1) What is k ?
2) What is ka ?
3) What is the elimination t1/2 ?
4) What is the absorption t1/2 ?
5) What is C0 ?
6) What is V ?
Compare general & patient specific equations:
1) k = 0.1 h-1
2) ka = 0.9 h-1
3) Elimination t1/2 = ln 2 / k = 0.693/k = 0.693/0.1 = 6.93 h
4) Absorption t1/2 = ln 2 / ka = 0.693/ka = 0.693/0.9 = 0.77 h
5) C0 = 0 (initial concentration at t = 0)
MATH: If t = 0 is substituted in the absorption model

equation C = 0
GRAPH: Looking at absorption model plot C vs. t it can be
seen that initial concentration is zero

6) Comparing general & patient specific equations
ANSWER : V = 13.6 L
Comment: Only one volume of distribution for one
compartment model
COMMENTS
(a)
can be written as
(b) A’ = 56 mg/L (units !!)
(c) ka >> k In example: 0.9 h-1 >> 0.1 h-1

C. ABSORPTION MODEL TERMS

ABSORPTION MODEL TERMS
 Cmax & tmax
 LAG TIME
 FLIP FLOP KINETICS

Cmax
tmax
Cmax and tmax
 Cmax is highest [drug] (peak level) which occurs
at time tmax (peak time)

Cmax and tmax
QUESTIONS
For previous cardiac drug example
1. What is tmax ?
2. What is Cmax ?

Cmax and tmax
1.

Cmax and tmax
2.

Cmax and tmax
Comments:
➢ See Cmax , tmax , and C0 in C vs. t plot
➢ Do estimated results for above parameters

make sense?
➢ Shouldn’t Cmax be 56 mg/L ?

LAG TIME
FLIP FLOP KINETICS

LAG TIME
 Delay in time for absorption , e.g., for an

orally ingested drug
 Causes for delay include stomach emptying

time, intestinal motility, others
 See graph with lag time
 For this course lag time calculations are not

considered
FLIP FLOP KINETICS
 Not common in marketed products,

can be seen in some drugs with very
fast elimination ( k >> ka )
 For this course flip flop calculation

cases are not considered
D. ABSORPTION MODEL
IN CLASS EXERCISES
IN CLASS EXERCISES

DATA I
DATA I

DATA I
Patient levels vs. time after oral administration
of four 250 mg antibiotic capsules (F 0.65)
Time (h) C (mg/L)
0.2 6.10
0.5 12.46
1.0 18.11
2.0 20.29
3.0 18.25
4.0 15.44
6.0 10.52
8.0 7.06
12.0 3.18
DATA I
1. Estimate k , ka and A’
2. What are the general & patient specific
equations ?
3. What is tmax and Cmax?
4. Looking at C vs. t plot do calculated
Cmax and tmax make sense?
5. Estimate V
DATA I
1. From feathering analysis:

k = 0.19789 h-1
ka = 1.2239 h-1
A’ = 34.2797 mg/L
Comment: Explain feathering qualitatively

DATA I
2. GENERAL
SPECIFIC

DATA I
3. tmax
Cmax

DATA I
4. DATA I highest [ ] is 20.29 mg/L at 2 h. It is
close to calculated Cmax 20.2 mg/L at tmax
~1.8 h using fitted curve, so calculated
parameters make sense
Comments:
1) Also look at C vs. t plot to check if calculated values make
sense
2) Highest observed [ ] is not necessarily the real Cmax

DATA I
5. Volume of distribution
V = 22.6 L
DATA II
DATA II

DATA II
Patient levels vs. time after oral intake of four
500 mg cancer drug tablets (F 0.3 , AU∞ 250 mg)
Time (h) C (mg/L)
0.2 2.42
0.5 5.17
1.0 8.05
2.0 10.25
3.0 10.37
4.0 9.78
6.0 8.19
8.0 6.73
12.0 4.52
DATA II
Estimate
1. CL
2. AUC
3. CLR
DATA II
From feathering analysis:
k = 0.09697 h-1
ka = 1.031626 h-1
A’ = 14.5394 mg/L

DATA II
GENERAL
SPECIFIC

DATA II
1. CLEARANCE
CL = kV (k 0.0970 h-1, find V)
V = 45.55 L
CL = kV = 0.0970 * 45.55 = 4.42 L/h

DATA II
2. AUC = FD/CL = 0.3 * 2000 mg / 4.42 L/h
= 136 mg-h/L
3. CLR = fR CL
fR = AU∞/FD = 250 mg /(0.3*2000) = 0.42
CLR = 0.42*4.42 = 1.84 L/h


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ABSORPTION MODEL

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

Some portions of lecture notes

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

2. Recognize pchem and clinical PK terms in the

3. Calculate pchem and clinical PK parameters using

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

B. EQUATION RECOGNITION EXAMPLE

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

1 compartment model ; V = volume of distribution (L)

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

❖ dC/dt = Rate In – Rate Out

❖ Rate In = Drug absorption rate (from GI into system)

❖ Rate Out = Drug elimination rate (from system)

C = Drug plasma level (mg/L)

Note: A’ is used as a constant, do not confuse with A used for amounts

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

3) What is the elimination t1/2 ?

4) What is the absorption t1/2 ?

4) Absorption t1/2 = ln 2 / ka = 0.693/ka = 0.693/0.9 = 0.77 h

MATH: If t = 0 is substituted in the absorption model

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

(b) A’ = 56 mg/L (units !!)

(c) ka >> k In example: 0.9 h-1 >> 0.1 h-1

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

 Cmax & tmax

 FLIP FLOP KINETICS

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

For previous cardiac drug example

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

➢ See Cmax , tmax , and C0 in C vs. t plot

➢ Do estimated results for above parameters

➢ Shouldn’t Cmax be 56 mg/L ?

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

 Delay in time for absorption , e.g., for an

 Causes for delay include stomach emptying

 See graph with lag time

 For this course lag time calculations are not

 Not common in marketed products,

 For this course flip flop calculation

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

1. From feathering analysis:

Comment: Explain feathering qualitatively

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

From feathering analysis:

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.

fR = AU∞/FD = 250 mg /(0.3*2000) = 0.42

CLR = 0.42*4.42 = 1.84 L/h

PHARMACOKINETICS/CONCORDIA/CAYETANO C0029 DR.