 

Mohd_kaleemullah
@msu.edu.my
After reading the topic, you should be able to:

 Differentiate the characteristics of linear and nonlinear

pharmacokinetics.

 Understand how nonlinearity can arise in pharmacokinetics.

 Understand thoroughly the pharmacokinetics of single

capacity-limited elimination.

 Understand how nonlinear pharmacokinetics is handled

clinically.
 Nonlinear Pharmacokinetics

 Pharmacokinetics :- It is defined as the kinetics of drug

absorption, distribution ,metabolism and excretion and
their relation ship with the pharmacological ,therapeutic
or toxicological response in man and animals.

 Linear pharmacokinetics :- Pharmacokinetic

parameters for a drug would not change when
different doses or multiple doses of a drug were given.

 Non linear pharmacokinetics :- Pharmacokinetic

parameters change with the size of administered dose.
Zero-Order Kinetics (Constant Rate Processes)
If n = 0, equation becomes:
dC/dt = -Ko Co
where Ko = zero-order rate constant (in mg/min)
Zero-order process can be defined as the one whose rate is independent of the
concentration of drug undergoing reaction i.e. the rate of reaction cannot be increased
further by increasing the concentration of reactants.

Finally C = Co – Ko t
First-Order Kinetics (Linear Kinetics)
If n = 1, equation becomes:
dC/dt = - K C
where K = first-order rate constant (in time–1 or per hour)

first-order process is the one whose rate is directly proportional to the concentration of
drug undergoing reaction i.e. greater the concentration, faster the reaction. It is because
of such proportionality between rate of reaction and the concentration of drug that a
first-order process is said to follow linear kinetics.
 LINEAR
PHARMACOKINETICS

INEAR PHARMACOKINETICS
 Linear Pharmacokinetics

» At therapeutic doses, the change in the amount of drug in

the body or the change in its plasma concentration due to
absorption, distribution, binding, metabolism or excretion, is
proportional to its dose, whether administered as a single
dose or as multiple doses.

» In such situation the rate processes are said to follw first

order or linear kinetics and all semilog plots of C Vs t for
different doses when collected for dose administered, are
superimposable.

» The important pharmacokinetic parameters viz. F, Ka, KE,

Vd, ClR, ClH which describes the time course of a drug in
the body remain unaffected by the dose.
 Dose-independent PK
When the dose is increased (or on chronic medication), the unaffected
pharmacokinetic parameters are:

Plasma elimination rate constant (klO)

Plasma elimination half life (t1/2)

Apparent volume of distribution (Vd)

Fraction of bioavailability (F)

Clearance (Cl)

Renal clearance (C1R)

Hepatic clearance (CIH)

Linear Pharmacokinetics

i.v. bolus i.v. bolus

100 µM
Log C

Log C
normalized
10 µM
by dose

1 µM 10 mg 100 mg
1 mg 1 mg

1h 1h
time time

 Drug plasma concentrations are proportional to the dose.

 Drug plasmaconcentration-time profiles are superimposable when

normalized to the dose.
Linear Pharmacokinetics

p. o. p. o.

Log C
Log C

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

tmax tmax time

time
 Drug plasma concentrations are proportional to the dose.
 tmax remains unchanged.
 Drug plasmaconcentration-time profiles are superimposable when
normalized to the dose.
 Characteristics of the plasma concentration–time profile for drugs
that display linear pharmacokinetic

Part (c) demonstrates that the area under the plasma concentration time curve (AUC) is
proportional to the dose.
 Mean Plasma
Conc
Time (hours) mg/L
1 137
6 120
12 103
24 76
48 42
72 23
96 12
144 3.7
 1. A single dose of a drug was given to a 50 kg person at
a dose level of 10 mg/kg (500 mg). Blood samples were
collected periodically and the unchanged drug (parent
drug) content in the samples was estimated.

 Calculate all possible pharmacokinetic parameters using

the data given below.

 Blood Data for IV administration Time Drug level in Blood

(hrs)

1 20.00
3 11.30
5 7.00
7 4.30
10 2.00
 Step 1: Plot the blood levels of the drug versus time data
on a semi-logarithmic graph paper taking time on X-axis
and concentration of drug in blood on logarithmic y axis.

 Step 2: Make the best fit of points to give a straight line.

Extend the straight line to cut the Y-axis, to give the initial
concentration of the drug, CO (i.e. zero-time concentration
of drug in blood).

Note: When log C vs time plot

Is made, the intercept is equal to
log CO. Therefore, CO will be
the anti-log of the intercept.
 Step 3: Find out the slope of the line as shown in the
figure. The slope is equal to K/2.303. Therefore the
elimination rate constant,

𝐿𝐿𝐿𝐿𝐿𝐿 𝐶𝐶2−𝐿𝐿𝐿𝐿𝐿𝐿 𝐶𝐶1 𝐿𝐿𝐿𝐿𝐿𝐿 2.0−𝐿𝐿𝐿𝐿𝐿𝐿 4.30

 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 = = -0.1086
𝑡𝑡2−𝑡𝑡1 10−7

 K = -slope x 2.303 = 0.1086 x 2.303 = 0.25 hr -1.

Elimination rate constant (K) = 0.25 hr -1.

 Step '4: Biological half-life (t112)

Biological half-life (t112) = 0.693/K = 0.693/0.25
= 2. 772 hrs
 Step 5: Volume of distribution (Vd)

The volume of distribution of the drug

𝐼𝐼𝐼𝐼 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 500000
𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 = = 19607.8 𝑚𝑚𝑚𝑚 = 19.6798 𝐿𝐿
𝐶𝐶𝐶 25.5

 Step 6: Area under the curve (AUC): Area under the blood
concentration-time curve is calculated by the trapezoidal
rule.
𝐶𝐶𝐶 25.5
 𝐴𝐴𝐴𝐴𝐴𝐴 = = = 102 𝑚𝑚𝑚𝑚. ℎ𝑟𝑟/𝑚𝑚𝑚𝑚
𝐾𝐾 0.25

 Step 7: Total body clearance, Cr

Total Body clearance, Cr = Vd . K
Cr= 19.6078 x 0.25 = 4.9 Liters / hr
PHARMACOKINETIC ANALYSIS IN
CLINICAL PRACTICE
Example A patient is to be given an 80-mg IV dose of gentamicin every 8 h.
A peak and a trough of 6 and 0.5 mg/L, respectively, are desired after the
first dose.

Two plasma concentrations obtained after the first dose are shown in Table.
Determine if the peak and trough after this dose meets the goal. If not,
suggest a more appropriate dose.
Solution
NON-LINEAR PK
 Nonlinear Pharmacokinetics

• Most of the rate processes follow first order kinetics

• For a few drugs it is observed that the elimination of

the drug appears to be zero order at high
concentrations and first order at low concentrations.
• That is 'concentration' or 'dose' dependent kinetics are
observed. At higher doses, which produce higher
plasma concentrations, zero order kinetics are
observed, whereas at lower doses the kinetics are
linear or first order.
 Nonlinear Pharmacokinetics

• This occurs especially with drugs which are

extensively metabolized.

• A typical characteristic of enzymatic reactions and

active transport is a limitation on the capacity of
the process.

• There is only so much enzyme present in the liver,

and therefore there is a maximum rate at which
metabolism can occur.
Nonlinear Pharmacokinetics

• A further limitation in the rate of metabolism can

be the limited availability of a co-substance or co-
factor required in the enzymatic process.

• This might be a limit in the amount of available

glucuronide or glycine, for example.

• Drug concentrations in the blood can increase

rapidly once an elimination process is saturated.

• This nonlinear pharmacokinetic behavior is also

termed dose-dependent pharmacokinetics.
Nonlinear Pharmacokinetics

• A number of drugs demonstrate saturation

or capacity-limited metabolism in humans.

• Examples of these saturable metabolic

processes include:
– glycine conjugation of salicylate.
– sulfate conjugation of salicylamide.
– acetylation of p-aminobenzoic acid.
– The elimination of phenytoin.
Characteristic of
Non-linear PK
 Nonlinear Pharmacokinetics

• Drugs that demonstrate saturation kinetics usually

show the following characteristics:
1) Elimination of drug does not follow simple first-order
kinetics—that is, elimination kinetics are nonlinear.
2) The elimination half-life changes as dose is increased.
Usually, the elimination half-life increases with
increased dose due to saturation of an enzyme
system. However, the elimination half-life might
decrease due to "self"-induction of liver
biotransformation enzymes, as is observed for
carbamazepine.
 Nonlinear Pharmacokinetics

3) The area under the curve (AUC) is not proportional

to the amount of bioavailable drug.

4) The saturation of capacity-limited processes may be

affected by other drugs that require the same
enzyme or carrier-mediated system (ie, competition
effects).

5) The composition and/or ratio of the metabolites of

a drug may be affected by a change in the dose.
 Nonlinear Pharmacokinetics

• When a large dose is given, a

curve is obtained with an initial
slow elimination phase followed
by a much more rapid
elimination at lower blood
concentrations (curve A).

• With a small dose of the drug,

apparent first-order kinetics are
observed, because no saturation
kinetics occur (curve B).
Plasma level–time curves for a drug
that exhibits a saturable elimination
process. Curves A and B represent high
and low doses of drug, respectively,
given in a single IV bolus.
 Nonlinear Pharmacokinetics

• If the pharmacokinetic data

were estimated only from the
blood levels described by
curve B, then a two fold
increase in the dose would
give the blood profile
presented in curve C, which
considerably underestimates
the drug concentration as well Plasma level–time curves for a drug
as the duration of action. that exhibits a saturable elimination
process. The terminal slopes of curves
A and B are the same. Curve C
represents the normal first-order
elimination of a different drug.
Nonlinear Pharmacokinetics

• In order to determine whether a drug is following

dose-dependent kinetics, the drug is given at
various dosage levels and a plasma level–time
curve is obtained for each dose.

• The curves should exhibit parallel slopes if the

drug follows dose-independent kinetics.
Alternatively, a plot of the areas under the plasma
level–time curves at various doses should be
linear.
 Nonlinear Pharmacokinetics

Area under the plasma level–time curve versus dose

for a drug that exhibits a saturable elimination process.
Curve A represents dose-dependent or saturable
elimination kinetics.
 Curve C represents dose-independent kinetics.
 Dose-dependent PK
When the dose is increased (or on chronic medication), deviation from linear
pharmacokinetics is observed as given below.

Plasma elimination rate constant (klO)

Plasma elimination half life (t1/2)

Apparent volume of distribution (Vd)

Fraction of bioavailability (F)

Clearance (Cl)

Renal clearance (C1R)

Hepatic clearance (CIH)

DETECTION OF NON-LINEARITY IN PHARMACOKINETICS

There are several tests to detect non –linearity in pharmacokinetics

but the simplest ones are:
1) First test:- Determination of steady state plasma
concentration at different doses.

2) Second test:- Determination of some important

pharmacokinetic parameters such as fraction
bioavailability, elimination half life or total systemic
clearance at different doses of drug. Any change in these
parameters is indicative to non-linearity which are
usually constant.
#
Linear vs Nonlinear Pharmacokinetics

Linear Nonlinear
(dose-dependent)
(dose-independent)
at least one of the ADME
ADME all obey first-order
processes is saturable.
kinetics.
≥1 PK parameters are dose-
 PK parameters (CL, V, F, Ka,
dependent.
and t1/2) are constant.
AUC is disproportional to the
AUC is directly proportional
dose.
to the dose.
Concentration vs. time profile is
Concentration vs. time
not superimposable for different
profile is superimposable for
doses.
all doses.
Implications of
Non-linear PK
 IMPLICATION OF NON-LINEARITY PK

1. A number of pharmacokinetic parameters change at high

doses of drugs. These may increase or decrease and
subsequently affect the therapy.

2. Inter-subject variability in pharmacologic response is

observed.

3. Plasma elimination half life determined from plasma data of

low-doses cannot be extrapolated to high-doses.

4. Special attention must be given to drug toxicity related

aspects due to altered pharmacokinetics. In therapeutic range,
phenytoin yields less predictable results in drug therapy and
precipitates toxic effects.
 IMPLICATION OF NON-LINEARITY PK

1. There is a need to alter the dose or frequency of

administration.

2. Individual patient should be given attention through

therapeutic drug monitoring (TDM).

3. The evaluation of bioavailability and bioequivalence

must be done case by case and dose by dose basis.
 Causes of
non-linearity
 CAUSES OF NON-LINEARITY
Drug absorption
•
Three causes:- I) Solubility / dissolution of drug is rate-limited;
Griseofulvin - at high concentration in intestine.

II) Carrier - mediated transport system; Ascorbic

acid - saturation of transport system.

III) Presystemic gut wall / hepatic metabolism

attains saturation; Propranolol.

• These parameters affected F, Ka, Cmaxand AUC.

• A decrease in these parameters is observed in former two causes

and an increase in latter cause.
Nonlinear Pharmacokinetics
e. g.
- 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.
Nonlinear Pharmacokinetics
e. g.
- Saturable transport across the intestinal epithelium

375 mg -Amoxicillin is actively transported

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

- 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.

43
 Drug distribution

At high doses non-linearity due to

• Two causes:- I) Binding sites on plasma proteins get
saturated; Phenylbutazone.

II) Tissue binding sites get saturated.

• In both cases there is increase in plasma drug

concentration.

• Increase in Vdonly in (I)

• Clearance with high ER get increased due to saturation of

binding sites.
 Drug metabolism

• Non-linearity occurs due to capacity limited metabolism, small

changes in dose administration - large variations in plasma
concentration at steady state - large intersubject variability.

• Two imp causes:- I) Capacity - limited metabolism - enzyme &/

cofactor saturation; Phenytoin, Alcohol.

II) Enzyme induction - decrease in plasma

concentration; Carbamazepine.

• Autoinduction in dose dependent concentration.

• Saturation of enzymes - decrease in ClH- increase in Css.
• In case of enzyme induction reverse condition.
• Other reasons includes saturation of binding sites, inhibitory
effects of the metabolites on the action of enzymes.
 Drug excretion
•

Two active processes which are saturable,

I) Active tubular secretion - Penicillin G
II) Active tubular reabsorption - Water soluble
vitamins & Glucose.

• Saturation of carrier systems - decrease in renal clearance in

case of I & increase in II. Half life also increases.
• Other reasons like forced diuresis, change in urine pH,
nephrotoxicity & saturation of binding sites.
• In case of biliary excretion non - linearity due to saturation -
Tetracycline & Indomethacin.
#
Common Sources for Nonlinear Pharmacokinetics
Common Sources for Nonlinear Pharmacokinetics
Michaelis–Menton
kinetics.
 Saturable Enzymatic Elimination Processes

• The elimination of drug by a saturable enzymatic

process is described by Michaelis–Menten kinetics.

• If Cp is the concentration of drug in the plasma,

then:
dC V C
Eliminatio n rate = P = max P
dt K M + CP

• Where:
– Vmax is the maximum elimination rate.
– KM is the Michaelis constant that reflects the capacity of
the enzyme system.
 Rate of metabolism vs concentration

Vmax Maximum rate of metabolism

100
Rate of metabolism units/day

80
Michaelis-Menten Equation

Vmax .C
60
Rate of metabolism = ------------
1/2 Vmax Km + C
40

20

0
0 Km 10 20Drug concentration
30 (units/L)
40 50
Concentration at ½ Vmax
 Saturable Enzymatic Elimination Processes

• KM is not an elimination constant, but is actually a

hybrid rate constant in enzyme kinetics,
representing both the forward and backward
reaction rates and equal to the drug concentration
or amount of drug in the body at 0.5Vmax.

• The values for KM and Vmax are dependent on the

nature of the drug and the enzymatic process
involved.
 Saturable Enzymatic Elimination Processes

• When the drug concentration Cp is large in relation to

KM (Cp >> Km), saturation of the enzymes occurs and
the value for KM is negligible.

• The rate of elimination proceeds at a fixed or

constant rate equal to Vmax. Thus, elimination of drug
becomes a zero-order process and Eq. becomes:

dCP Vmax CP
Elimination rate = - = =Vmax
dt CP
Saturable Enzymatic Elimination Processes

• When the drug concentration Cp is small in

relation to the KM, the rate of drug elimination
becomes a first-order process.

− dCP V C V
= max P = max C P = k′CP
dt CP + K M K M

Where: k' is a first-order rate constant for a saturable process

 Saturable Enzymatic Elimination Processes

• When given in therapeutic doses, most drugs

produce plasma drug concentrations well below KM
for all carrier-mediated enzyme systems affecting
the pharmacokinetics of the drug.

• Therefore, most drugs at normal therapeutic

concentrations follow first-order rate processes.
Saturable Enzymatic Elimination Processes

• Only a few drugs, such as salicylate and

phenytoin, tend to saturate the hepatic mixed-
function oxidases at higher therapeutic doses.

• With these drugs, elimination kinetics are first-

order with very small doses, mixed order at
higher doses, and may approach zero-order with
very high therapeutic doses.
Saturable Enzymatic Elimination Processes

Linear Plot of Cp Versus Time

Showing High Cp and Low Cp –
Zero Order and First Order Elimination
Saturable Enzymatic Elimination Processes

Semi-Log Plot of Cp Versus Time

Showing High Cp and Low Cp
 Estimation of Doses and Plasma Concentrations

 Example A patient is to begin taking phenytoin. A steady plasma

concentration of 15 mg/L is desired. Assuming a Vmax of 400
mg/day and a Km value of 4 mg/L, what rate of administration of
phenytoin sodium (S = 0.92, F = 1) should be used?