Non-Linear Pharmacokinetics

Non-linear pharmacokinetic models, as opposed to linear pharmacokinetic models differ

in some very critical areas. When the concentration that results from the dose is
proportional to that dose and the rate of elimination of the drug is proportional to the
concentration, the drug is said to exhibit linear pharmacokinetics as shown below.

Figure 13-1-1 Figure 13-1-2

30
100

25
75
20

Cp (ng/mL)
Cp (ng/mL)

15 50

10
25
5

0 0
0 5 10 15 20 25 30
0 5 10 15
Dose (mg) Time (hr)

Dose
Cp ∝ Dose = (13.1.1)
Volume
∂Cp
− ∝ Cp (13.1.2)
∂Time

Integrating equation (13.1.2) results in the first order equation:

Cp = Cp0 e − KT (13.1.3)
which can be rewritten to
LN (Cp) = LN (Cp0 ) − KT (13.1.4)
A graph of which is linear with time as shown below.

Figure 13-1-3

100
Cp (ng/mL)

10

1
0 5 10 15 20 25 30

Time (hr)
When concentration that results from the dose is not proportional to that dose and/or the
rate of elimination of the drug is not proportional to the concentration, the drug is said to
exhibit non-linear kinetics as shown below.
Figure 13-1-5
Figure 13-1-4

1000
100
900
90
800
80
Cp (ng/mL) ave

70 700

Cp (ng/mL)
60 600
50 500
40 400
30
300
20
200
10
100
0
0
0 100 200 300 400 500 0 10 20 30 40

Dose/day Time (hours)

If we were to plot LN(Cp) vs Time as in figure (13.1.4), we would observe the following:

Figure 13-1-6

1000

100
Cp (ng/mL)

10

1
0 10 20 30 40
Time (hours)

Compare the terminal portion of the curve (time>25 hours) of figures 5 and 6 with figures
2 and 3. Looks similar, doesn’t it. Well, there’s a reason for it. In many cases, the rate
of elimination of the drug is defined by the enzymatic metabolism. From biochemistry,
we (should) remember the Michaelis-Menten equation that describes the rate of substrate
metabolism.
∂C V C
= − max (13.1.5)
∂t ( Km + C )
Where Vmax = the maximum velocity capable by the enzymes
Km = drug concentration that is metabolized at half the
maximum velocity
Drugs that exhibit this kind of behavior are said to exhibit non-linear pharmacokinetics.
Let’s look at the various portions of the curve. There are three distinct portions of this
curve:
1) The initial straight portion of the figure 13-1-5 (Cp >> Km)
2) The middle curved portion of figure 13-1-5 and 13-1-6 (Cp ≈ Km)
3) The terminal straight portion of figure 13-1-6 (Cp << Km)

If (Cp >> Km) then equation (13.1.5) becomes:

∂C V C
 − max = −Vmax = − KC 0 (13.1.6)
∂t (C )
What we see is that the enzymatic activity is maxed out and the rate of elimination of the
drug is constant or, in math speak, the elimination rate is proportional to C to the zero
power. (Math review A0=1, Chapter 2.) Thus − KC 0 = − K . Drugs that exhibit this kind
of behavior are said to exhibit zero order behavior. The concentration is changed at a
constant rate, X mg/hour are removed by the metabolizing enzymes.

If (Cp << Km) then equation (13.1.5) becomes:

∂C V C
= − max = − KC1 (13.1.7)
∂t ( Km )
Vmax
where =K
( Km )
Drugs that exhibit this kind of behavior are said to exhibit first order behavior. The
concentration is changed at a rate proportional to the concentration, X%/hour is removed
by the metabolizing enzymes.

Note equation (13.1.7) is identical to equation (13.1.2). Thus, what we see for a majority
of drugs is that equations (13.1.3) and (13.1.4) describe their pharmacokinetics because
the enzymes in the body are very efficient in the drug’s removal and the therapeutic
concentrations are well below the drug’s Km.

If (Cp ≈ Km) then the whole equation must be used and not just the limits as shown
above.

Why is this important? Because for those drugs where this is occurring, unlike drugs that
exhibit linear kinetics, where a change in daily dose results in a proportional change in
plasma concentration, as in the initial portion of figure 13-1-4 (< 200 mg/day), a small
change in daily dose could result in a LARGE change in plasma concentration, as shown
in the terminal portion of figure 13-1-4 (> 400 mg/day). In other words something like a
10% change in dose would not yield a 10% change in concentration but could yield a
100% (or greater) change in concentration. This could lead to toxicity.
At steady state, the rate of drug being put into the body equals the rate of drug
being removed from the body by the enzymes, thus:

fD Vmax Cpss
RateIn = DailyDose = = = RateOut (13.1.8)
τ ( K m + Cpss )

where tau = one day.

Multiplying (13.1.8) by (Km+Cpss)

DD ⋅ Km+DD ⋅ Cpss =Vmax Cpss (13.1.9)
Where DD = Daily Dose

Divide (13.1.9) by Cpss

DD
K m + DD = Vmax (13.1.10)
Cpss
Rearanging (13.1.10)
DD
DD = Vmax − Km (13.1.11)
Cpss
And
mg
DD day Liter
= = = Clearance (13.1.12)
Cpss mg Day
Liter
So:
DD = Vmax − Clearance ⋅ K m (13.1.13)

Thus, the daily dose is proportional to the clearance, and a graph of Daily Dose vs.
Clearance will result in a straight line with an intercept of Vmax and a slope of - Km.

Example: Your patient is 90 Kg male and the doctor would like to achieve a Cpss of 18
mg/L of Phenytoin. Previously you patient received a dose of 400 mg/day Dilantin
Kapseals and attained a Cpss of 7.7 mg/L and a dose of 600 mg/day to attain a Cpss of
15.3 mg/L. Find Vmax, Km and the daily dose necessary to accieve the desired blood
level.
First of all Dilantin Kapseals are Sodium Phenytoin and must be converted to
Phenytion equivalents:
Molecular Weight of Sodium Phenytoin is 274.25 g/mole and the molecular
weight of Phenytoin is 252.27 g/mole. So, the daily dose of Phenytoin in each
case is calculated by:

MW Phenytoin
Mg Phenytoin = mg Phenytoin Sodium * (13.1.14)
MW Phenytoin Sodium
Where the Molecular Weight of Sodium Phenytoin is 274.25 g/mole and the
molecular weight of Phenytoin is 252.27 g/mole.

So: Converting Sodium Phenytoin to phenytoin using (13.1.15) and Calculating

clearance using (13.1.12) yields the following data:

Dosage Sodium Phenytoin Phenytoin Cpss Clearance

Regimen (mg/day) (mg/day) (mg/Liter) (L/day)
1 400 367.94 7.7 47.78
2 600 551.91 15.3 36.07

which can be graphically represented by:

Figure 13-1-7
y = -15.711x + 1118.6
600
500
Daily Dose (mg)

400
300
200
100
0
0 20 40 60
Clearance (L/ay)

The trend line yields a Km of 15.7 mg/L and a Vmax of 1118.6 mg/day. Plugging in the
values of Km and Vmax into equation (13.1.8)

Vmax Cpss 1118.6 mg day ⋅18 mg Liter

DailyDose = = (13.1.16)
( K m + Cpss ) 15.7 mg Liter + 18 mg Liter
we find that the daily dose needed to attain a Cpss of 18 mg/L of Phenytion is:
Daily Dose Daily Dose
(mg Phenytoin) (mg Sodium Phenytoin)
597.47 649.53

Whereas if the drug exhibitd linear kinetics and we wanted to increase the plasma
concentration from 15.3 mg/Liter to 18 mg/Liter the dose of Sodium Phenytion would be
= 705.88 mg. If we did dose our patient at this daily dose a further rearrangement of
equation (13.1.9) yields:
DD ⋅ K m
Cpss = (13.1.17)
Vmax − DD
Converting 705.88 mg of Sodium Phenitoin to Phenytoin yields 651.76 mg/Phenytoin.
Plugging that into equation (13.1.17) yields a plasma concentration of 21.92 mg/Liter
instead of the intended 18 mg/Liter. In other words, an 18% increase in dose
(652/552=1.18) yields a 44% increase in plasma concentration (22/15.3 = 1.44.) This
clearly could be a problem.
Problems:
Cefadroxil
Sanchez-Pico, A., et al, "Nonlinear intestinal abosrption kinetics of cefadroxil in
the rat", Journal of Pharmacy Pharmacology, Vol.41, (1989), p. 179 - 185.

Cefadroxil is a cephalosporin antibiotic which is commonly used to treat

various infections. It is usually given orally. This study looks at the
pharmacokinetics and bioavailability of cefadroxil in the rat.

Dose C pss
µg
500 mg 7.31
mL
µg
1000 mg 14.67
mL

1. Find km .

2. Find the maximum clearance, v max , for this patient.

3. What would be the dose needed to acheive a steady-state concentration of

µg
10 ?
mL

4. You recommend changing the patient's dosage regimen to 300 mg/day.

What would be your patient's steady state plasma concentration?
 CD4
Qian, M., et al., "Pharmacokinetic evaluation of drug interactions with anti-human
immunodeficiency virus drugs: V. effect of soluble CD4 on 2',3'-dideoxycytidine
kinetics in monkeys", Drug Metabolism and Disposition, Vol. 20, (1992), p. 396 - 400.

2',3'-dideoxycytidine in combination with recombinant ST4 has been

shown to be effective against HIV (human immunodeficiency virus) in vitro. This
study examines whether or not the pharmacokinetics of 2',3'-dideoxycytidine are
affected by administration of CD4 (an immunoglobulin). Doses of each drug
were given to male adult monkeys weighing an average of 4.45 kg. The
following data is for ST4 (soluble CD4).

Dose C pss
µg
1.1 mg/kg 10.27
mL
µg
2.2 mg/kg 22.23
mL

Weight of Monkey = 4.45 kg

1. Find km .

2. Find the maximum clearance, v max , for this patient.

3. What would be the dose needed to acheive a steady-state concentration of

µg
15 ?
mL

4. You recommend changing the patient's dosage regimen to 1.5 mg/ kg.
What would be your patient's plasma concentration?
 Methylprednisone
Haughey, D, and Jusko W.., "Bioavailability and nonlinear dispositionof methylprednisolone and
methylprednisone in the rat", Journal of Pharmaceutical Sceicnes, Vol. 81, (1992), p. 117 - 121.

Methylprednisone is a corticosteroid which is commonly used in the

treatment of medical emergencies such as cardiovascular shock, asthma, and
cerebral edema. The following data was obtained for two methylprednisolone
doses. The plasma concentration measurement given for each dose below is
that for the central compartment.

Dose C pss
ng
10 mg 6834
mL
nmol
50 mg 71519
L

1. Find km .

2. Find the maximum clearance, v max , for this patient.

3. What would be the dose needed to acheive a steady-state concentration of

ng
10,000 ?
mL

4. You recommend changing the patient's dosage regimen to 30 mg. What

would be your patient's plasma concentration?
 Mezlocillin
Jungbluth, G. and Jusko, W., "Dose-dependent pharmacokinetics of mezlocillin in
rats", Antimicrobial Agents and Chemotherapy, Vol. 33, (1989), p. 839 - 843.

Mezlocillin is an antibiotic used to treat various types of infection. It is

usually given by the intravenous route and exhibits dose-dependent (nonlinear)
pharmacokinetics. This article compares two intravenous bolus doses, one of 20
mg/kg and one of 200 mg/kg in rats. The following data was calculated from the
results of this study.

Dose C pss
µg
20 mg/kg 158.6
mL
µg
200 mg/kg 294.1
mL

Rat weight = 425 g

1. Find km .

2. Find the maximum clearance, v max , for this patient.

3. What would be the dose needed to acheive a steady-state concentration of

µg
200 ?
mL

4. You recommend changing the patient's dosage regimen to 150 mg/ kg.
What would be your patient's plasma concentration?
 Naphthol
Redegeld, A., Hofman, G., and Noordhoek, J., "Conjugative clearance of 1-naphthol and
disposition of its glucuronide and sulfate conjugates in the isolated perfused rat",
Journal of Harmacology and Experimental Therapeutics, Vol. 244, (1988), p. 263 - 267.

1-naphthol is a small phenolic compound which is extensively metabolized

by conjugation. This study looks at the pharmacokinetics of naphthol in a rat.

Dose C pss
30 µmol 6.79 µM
40 µmol 8.63 µM

1. Find km .

2. Find the maximum clearance, v max , for this patient.

3. What would be the dose needed to acheive a steady-state concentration of

7.7 µM?

4. You recommend changing the patient's dosage regimen to 35 µmol. What

would be your patient's plasma concentration?
 Paroxetine
Sindrug, S., Brosen, K, and Gram, L.., "Pharmacokinetics of the selective serotonin reuptake
inhibitor paroxetine: nonlinearity and relation to the sprateine oxidation polymorphism", Clinical
Pharmacology and Therapeutics, Vol. 51, (1992), p. 288 - 295.

Paroxetine hydrochloride (Paxil) is a selective serotonin reuptake

inhibitor which is used in the treatment of depression. Paroxetine is metabolized
both by oxidation and conjugation with the conjugated metabolites excreted in
the urine. Paroxetine exhibits dose-dependent (nonlinear) pharmacokinetics.
The following data is for a male diabetic patient who was concurrently taking
insulin.

Dose C pss
ng
10 mg daily 1.65
mL
ng
20 mg daily 3.30
mL
ng
30 mg daily 8.25
mL
ng
40 mg daily 13.20
mL
ng
50 mg daily 26.40
mL
ng
60 mg daily 39.60
mL
ng
70 mg daily 66.00
mL

1. Find km .

2. Find the maximum clearance, v max , for this patient.

3. What would be the dose needed to acheive a steady-state concentration of

µg
50 ?
mL

4. You recommend changing the patient's dosage regimen to 36 mg/day.

What would be your patient's plasma concentration?
 Phenytoin
Levine, M., et al., "Evaluation of serum phanyton monitoring in an acute
care setting", Therapeutic Drug Monitoring, Vol. 10, (1988)., p. 50 - 57.

Phenytoin is an agent which is commonly used in the treatment of

epilepsy. This drug exhibits nonlinear kinetics. Phenytoin is mainly eliminated
from the body by hepatic cytochrome P-450 metabolism. Several doses of
phenytoin were studied in patients and the data is summarized below:

Dose Day C pss

300 mg at bedtime mg
2 5.0
(started on day 1) L
200 mg BID mg
12 11.4
(started on day 6) L
200 mg BID mg
49 21.5
(started on day 6) L

1. Find km .

2. Find the maximum clearance, v max , for this patient.

3. What would be the dose needed to acheive a steady-state concentration of

mg
15 ?
L

4. You recommend changing the patient's dosage regimen to 300 mg/day.

What would be your patient's plasma concentration?
 Phenytoin in the Critically Ill
Boucher, B. et al., "Phenytoin pharmacokinetics in critically ill trauma patients",
Clinical Pharmacology and Therapeutics, Vol. 44, (1988)., p. 675 - 683.

Phenytoin is an agent which is commonly used in the treatment of

epilepsy. This drug exhibits nonlinear kinetics. This study looks at several doses
of phenytoin in severely ill trauma patients. The data given below is that
obtained for one male, 25 year-old, patient who weighed 85 kg.

Dose C pss
mg
615 mg/ day 10
L
mg
588 mg/day 8.5
L

1. Find km .

2. Find the maximum clearance, v max , for this patient.

3. What would be the dose needed to acheive a steady-state concentration of

mg
12 ?
L

4. You recommend changing the patient's dosage regimen to 450 mg/ day.
What would be your patient's steady-state plasma concentration?
 Phenytoin in Pediatrics
Bauer, L. and Blouin, R., "Phenytoin Michaelis-Menten pharmacokinetics in caucasian
paediatric patients", Clinical Pharmacokinetics, Vol. 8, (1989)., p. 545 - 549.

Phenytoin is an agent which is commonly used in the treatment of

epilepsy. This drug exhibits nonlinear kinetics. This study looks at several doses
of phenytoin in pediatric patients of several ages. The data for the 4 to 6 year old
patients is given below.

Dose C pss
µg
7.5 mg/ kg/ day 15
mL
µg
6.5 mg/ kg/day 10
mL

1. Find km .

2. Find the maximum clearance, v max , for this patient.

3. What would be the dose needed to acheive a steady-state concentration of

mg
12 ?
L

4. You recommend changing the patient's dosage regimen to 4.5 mg/ kg/ day.
What would be your patient's steady-state plasma concentration?
 Quinalapril
Elliott, H., et al., "Dose responses and pharmaockinetics for the angiotensin converting enzyme
inhibitor, quinapril", Clinical Pharmacology and Therapeutics, Vol. 52, (1992), p. 260 - 265.

Quinalapril is an angiotensin converting enzyme (ACE) inhibitor which is

used in the treatment of hypertension and heart failure. The optimal dosage
regimen for the ACE inhibitors is controversial and this study further investigates
quinalapril's pharmacokinetics at various doses ranging from 0.5 to 20 mg.
Quinalapril is a prodrug which is metabolized to its active form, quinalaprilat.

Dose C pss
(of quinalapril) (of quinalaprilat)
ng
2.5 mg daily 47.5
mL
ng
5.0 mg daily 98.1
mL

1. Find km .

2. Find the maximum clearance, v max , for this patient.

3. What would be the dose needed to acheive a steady-state concentration of

ng
75 ?
mL

4. You recommend changing the patient's dosage regimen to 3.0 mg/day.

What would be your patient's plasma concentration?
 Vanoxerine
Ingwersen, S., et al., "Nonlinear multiple-dose pharmacokinetis of the dopamine reuptake
inhibitor vanoxerine", Journal of Pharmaceutical Sciences, Vol. 82, (1993)., p. 1164 - 1166.

Vanoxerine is a pre-synaptic dopamine reuptake inhibitor which may be

useful as an antidepressant. The bioavailability of vanoxerine is changed by food
intake. The bioavailability after fasting is increased 76% by a low-fat meal and
255% by a high-fat meal. In this study, the volunteers were given doses of
vanoxerine after eating a standard breakfast of one bowl of cereal with milk, two
slices of toast with sunflower margarine and jam, and one cup of tea.

Dose C pss
nmol
25 mg 3.4
L
nmol
75 mg 15.1
L
nmol
125 mg 46.5
L

1. Find km .

2. Find the maximum clearance, v max , for this patient.

3. What would be the dose needed to acheive a steady-state concentration of

nmol
30.0 ?
L

4. You recommend changing the patient's dosage regimen to 100 mg. What
would be your patient's plasma concentration?
 Nonlinear Equations

The following equations were used to solve the questions following

each "nonlinear" scenario. Three scenerios have been completed for
you. The answers have been provided for the remainder.
1.
D1 − D2
km =
D1 D2
ss
− ss
Cp Cp
1 2

Where:
D = Dose
Cpss = Steady - state plasma concentration

2.

Vmax =
(
D km + Cpss )
Cpss
Where:
Vmax = maximum clearance
km = Michaelis - Menten Rate Constant

Vmax ⋅ Cpss
3. D=
km + Cpss

D ⋅ km
4. Cpss =
Vmax − D
 Phenytoin in the Critically Ill
D1 − D2 615 mg − 588 mg mg
1. km = = = 3.517
D1 D2 615 mg 588 mg L
− ss −
Cpss
Cp mg mg
1 2
10 8.5
L L

 mg mg 
2. Vmax =
(
D km + Cpss ) = 615 mg  3.517 L
+ 10 
L 
= 831.3 mg
Cpss mg
10
L

mg
Vmax ⋅ Cpss . mg ⋅ 10
8313
3. D= = L = 642.88 mg
km + Cpss mg mg day
3.517 + 10
L L

mg
D ⋅ km 450 mg ⋅ 3.517
4. Cpss = = L = 4.15 mg
Vmax − D 8313. mg − 450 mg L
________________________________________________________________
_____
 CD4
1. The monkeys had an average weight of 4.45 kg.
mg
D1 = 2.2 • 4.45 kg = 9.79 mg
kg
mg
D1 = 11
. • 4.45 kg = 4.895 mg
kg
µg mg
Cpss = 22.23 = 22.23
1 mL L
ss µg mg
Cp = 10.27 = 10.27
2 mL L
D − D2 9.79 mg − 4.895 mg mg
km = 1 = = 135.09
D1 D2 9.79 mg 4.895 mg L
− ss −
Cp ss
Cp mg mg
1 2
22.23 10.27
L L

 mg mg 
2. Vmax =
(
D km + Cpss
=
)
9.79 mg  135.09
 L
+ 22.23 
L 
= 69.28 mg
Cpss mg
22.23
L

µg mg
3. Cpss = 15 = 15
mL L
mg
Vmax ⋅ Cpss 69.28 mg ⋅ 15 mg
D= = L = 6.92
km + Cpss mg mg day
135.09 + 15
L L

mg
4. D = 15
. • 4.45 kg = 6.675 mg
kg
mg
D ⋅ km 6.675 mg ⋅ 135.09
Cpss = = L = 14.40 mg
Vmax − D 69.28 mg − 9.79 mg L
_____________________________________________________________________
 Cefadroxil

µg mg
1. Cpss = 14.67 = 14.67
1 mL L
µg mg
Cpss = 7.31 = 7.31
2 mL L
D1 − D2 1000 mg − 500 mg mg
km = = = 2144.75
D1 D2 1000 mg 500 mg L
− ss −
Cpss
Cp mg mg
1 2
14.67 7.31
L L
 mg mg 
2. Vmax =
(
D km + Cpss
=
)
500 mg  2144.75
 L
+ 7.31 
L 
= 147200 mg = 147.2 g
Cpss mg
7.31
L

µg mg
3. Cpss = 10 = 10
mL L
mg
Vmax ⋅ Cpss 147200 mg ⋅ 10 mg
D= = L = 683.14
km + Cpss mg mg day
2144.75 + 10
L L

mg
D ⋅ km 300 mg ⋅ 2144.75
4. Cpss = = L = 4.38 mg
Vmax − D 147200 mg − 300 mg L
 Answers
Cefadroxil Phenytoin
1. 2144.75 µ g
mL 1. 4.014 µ g
mL
2. 147.2 g/day
3. 683.14 mg 2. 540.85 mg/day
3. 426.7 mg/day
4. 4.38 µ g
mL 4. 5 µg
mL

CD4 Phenytoin in the

1. 135.09 µ g
mL
Critically Ill
2. 69.28 mg/day 1. 3.517 µ g
3. 6.92 mg/day mL
4. 14.4 µ g 2. 831.3 mg/day
mL 3. 642.88 mg/day
4. 4.15 µ g
Methylprednisone mL

1. 52345.27 ng
mL
Phenytoin in
2. 86.60 mg/day Pediatrics
3. 13.89 mg/day
1. 6.67 µ g
4. 27747.1 ng mL
mL
2. 162.5 mg/day
3. 104.46 mg/day
Mezlocillin
4. 4.74 µ g
mL
1. 324.95 µ g
mL
2. 25.92 mg/day Quinalapril
3. 68.23 mg/day
1. 1503.15 ng
4. 1676.04 µ g mL
mL
2. 81.61 mg/day
3. 3.88 mg/day
Naphthol
4. 57.36 ng
1. 46.14 µM mL
2. 233.86 µmol
3. 25.61 µmol Vanoxerine
4. 43.5 µM
1. 20.96 nm ol
L
Paroxetine 2. 179.08 mg/day
3. 105.4 mg/day
1. 4.125 ng
mL 4. 26.5 nm ol
2. 45 mg/day L
3. 41.6 mg/day
4. 16.5 ng
mL