Nonlinear

Pharmacokinetics

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 Case Study

An epileptic patient who has not responded to

phenytoin after 2 weeks on 300 mg/day is observed to have a
plasma concentration of 4 mg/ml. Twenty days after the daily
dose is subsequently increased to 500 mg/day, the patient
develops severe toxicities. The plasma concentrations of
phenytoin is now 36 mg/mL.
 Review of Linear Pharmacokinetics

 ADME all obey first-order kinetics

 Pharmacokinetic parameters, e.g. elimination half-life (t1/2),

the elimination rate constant (k), the apparent volume of
distribution (V) and the clearance (CL) remain constant.

 Plasma drug concentration at a given time and AUC are

directly proportional to the dose.

 Concentrations of drug in plasma and tissues are below

protein binding saturation 3
 Review of Linear Pharmacokinetics

i.v. bolus i.v. bolus

100 mM
Log C

Log C
normalized
10 mM
by dose

1 mM 100 mg
10 mg 1 mg
1 mg
1h 1h
time time

 Drug plasma concentrations are proportional to the dose.

 Drug plasma concentration-time profiles are superimposable when
normalized to the dose.
 Review of Linear Pharmacokinetics

p. o. p. o.

Log C
Log C

2.5 mM normalized
0.5 mM by dose
25 mg
0.1 mM 0.1 mM
5 mg
1 mg 1 mg

tmax time tmax time

 Drug plasma concentrations are proportional to the dose.
 tmax remains unchanged.
 Drug plasma concentration-time profiles are superimposable when
normalized to the dose.
 Review of Linear Pharmacokinetics

VD or CL or t1/2
Cp or AUC

Dose Dose

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 Nonlinear Pharmacokinetics

i.v. bolus i.v. bolus

800 mM

100 mg
Log C

Log C
normalized
20 mM
by dose 8 mM
10 mg 2 mM
1 mM 1 mM
1 mg 100 mg
1 mg 10 mg
1h 1h
time time

 Drug plasma concentrations are not proportional to the dose.

 Drug plasma concentration-time 7profiles are not superimposable
when normalized to the dose.
 Nonlinear Pharmacokinetics

p. o. p. o.
10 mM

5 mM normalized
Log C

1 mM

Log C
1 mM by dose
0.5 mM
100 mg
0.1 mM 1 mg
10 mg
10 mg
1 mg 100 mg

time time
 Drug plasma concentrations are not proportional to the dose.
 tmax may or may not change.
 Drug plasma concentrations are not superimposable when
normalized to the dose.
Common Sources for Nonlinear Pharmacokinetics

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 Linear vs. Nonlinear Pharmacokinetics
Linear Nonlinear
(dose-independent) (dose-dependent)

 ADME all obey first-order  at least one of the ADME

kinetics. processes is saturable.

 PK parameters (CL, V, F, Ka,  ≥1 PK parameters are dose-

and t1/2) are constant. dependent.

 AUC is directly proportional to  AUC is disproportional to the

the dose. dose.

 Concentration vs. time profile  Concentration vs. time profile is

is superimposable for all doses. not superimposable for different
doses.
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Most Common Sources for Nonlinear Pharmacokinetics

 Capacity-limited oral absorption (F)

 Capacity-limited metabolism (CLH )

 Saturable protein binding (CLH, CLR, V )

 Capacity-limited excretion (CLR )

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 Capacity-Limited Oral Absorption (F)

 limited dissolution/solubility as the oral dose increases

 saturable transport across the intestinal mucosa as the oral dose

increases

 saturable first-pass metabolism in the intestinal epithelium (gut

wall) and/or liver as the oral dose increases

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 - limited dissolution/solubility in the GI tract
normalized
to the dose

- Griseofulvin is poorly water-

soluble (10 mg/L).
- Less proportion of the drug
is being dissolved and
absorbed with the higher
dose.
- F decreases as the dose
increases.
- tmax remains the same.

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.

- Saturable transport across the intestinal epithelium

375 mg

- Amoxicillin is actively transported by

750 mg peptide transporter in the small
intestine.
1500 mg - The active transport becomes
saturated as the dose increases.
3000 mg
- F decreases as the dose increases.
- tmax remains the same.

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- Saturable first-pass metabolism

- Nicardipine is metabolized by CYP3A4 in the intestinal epithelium

and hepatocytes.
- First-pass metabolism is saturated as the dose increases.
- F increases as the dose increases.
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- Saturable first-pass metabolism

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 Saturable Drug-Plasma Protein binding (CL,V)

 Drug-plasma protein binding is saturable

The saturation drug concentrations for binding with plasma albumi

and a1-acid glycoprotein are ~ 600 mM and 15 mM, respectively.

 May increase CLH and/or CLR

 May increase V

 May be difficult to identify due to effect on both V and CL

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 Capacity-Limited Excretion (CLR)

 Active secretion and active reabsorption are saturable

processes.

 Saturated tubular secretion decreases CLR

Saturated tubular reabsorption increases CLR

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Capacity-Limited Metabolism (CLH ,F)

 Enzymatic reactions are saturable.

 Saturated hepatic metabolism decreases CLH.

 Saturated first-pass metabolism increases F.

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e. g.
- capacity-limited metabolism
- Phenytoin is eliminated by
hepatic metabolism only.
- As the dosing rate
increases, Cp increases
disproportionally.
- As the dosing rate
increases, hepatic
metabolism is saturated and
CL decreases.
- As the dosing rate
increases, it takes longer
time to reach steady state.
FD
 CL Css
 20
Most Common Sources for Nonlinear Pharmacokinetics

 Capacity-limited oral absorption (F)

 Capacity-limited metabolism (CLH )

 Saturable protein binding (CLH, CLR, V )

 Capacity-limited excretion (CLR )

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