NON LINEAR

PHARMACOKINE
TICS
Part 1
• INTRODUCTION:
• Linear models assumed that the pharmacokinetic
parameters for a drug would not change when different
doses or multiple doses of a drug were given.
• But with some drugs, increased doses or chronic
medication can cause deviations from the linear
pharmacokinetic profile previously observed with
single low doses of the same drug.
• This nonlinear pharmacokinetic behavior is also termed
dose-dependent pharmacokinetics.
Drugs that demonstrate saturation kinetics show the
following characteristics.
1. Drug elimination does not follow first-order kinetics.

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

3. Saturation of an enzyme system may be due to

competition of drugs for metabolism.(competition effects)
Plasma level–time curves for
a drug that exhibits a
saturable elimination
process.
Curves A and B represent
high and low doses of durg,
respectively, given in a
single IV bolus.
Curve C represents the
normal first-order
elimination of a different
drug.
SATURABLE ENZYMATIC
ELIMINATION PROCESSES
• The elimination of drug by a saturable enzymatic process
is described by Michaelis–Menten kinetics.
• If C p is the concentration of drug in the plasma, then
Elimination rate = dCp = VmaxCp
dt KM+Cp
• Vmax is the maximum elimination rate
• KM is the Michaelis constant that reflects the capacity of
the enzyme system. It is equal to the drug concentration or
amount of drug in the body at 0.5V max .
• The values for KM and Vmax are dependent on the nature
of the drug and the enzymatic process involved.
• When the drug concentration C p is large in relation to K M (C p >>
K m), saturation of the enzymes occurs and the value for K M is
negligible.
• The rate of elimination proceeds at a fixed or constant rate equal to V
max .
• Thus, elimination of drug becomes a zero-order process and Equation
becomes:

- dCp = VmaxCp = Vmax

dt Cp
DETERMINATION OF KM AND
VMAX:
•  (Eq 1)
relates the rate of drug biotransformation to the
concentration of the drug in the body.
When an experiment is performed with solutions of
various concentration of drug C,
 a series of reaction rates (v) may be measured for each
concentration.
Special plots may then be used to determine Km and
Vmax.
• Equation 2 may be rearranged into Equation 3.
(Eq 2)

(Eq 3)
Equation 3is a linear equation when 1/v is plotted against 1/C. The
y intercept for the line is 1/Vmax, and the slope is KM/Vmax
A plot of 1/v versus 1/C is shown.
 :

•  
An example for the determination of KM and Vmax is given for
the drug phenytoin.

 Phenytoin undergoes capacity-limited kinetics at therapeutic drug

concentrations in the body.

To determine KM and Vmax, two different dose regimens are given at
different times, until steady state is reached.

The steady-state drug concentrations are then measured by assay.

 At steady state, the rate of drug metabolism (v) is assumed to be

the same as the rate of drug input R (dose/day).
Therefore, Equation 4 may be written for drug metabolism in the
body similar to the way drugs are metabolized in vitro (Equation 2).

However, steady state will not be reached if the drug input rate, R,
is greater than the Vmax; instead, drug accumulation will continue
to occur without reaching a steady-state plateau

Eq 4:
Where,
R = dose/day or dosing rate,
Css = steady-state plasma drug concentration,
Vmax = maximum metabolic rate constant in the body,
KM = Michaelis–Menton constant of the drug in the body.
Dependence of Elimination Half-Life on Dose:

• For drugs that follow linear kinetics, the elimination half-life is

constant and does not change with dose or drug concentration.

• For a drug that follows nonlinear kinetics, the elimination half-

life and drug clearance both change with dose or drug
concentration.

• Generally:
 the elimination half-life becomes longer,
 clearance becomes smaller,
 and the area under the curve becomes disproportionately larger
with increasing dose.
• The relationship between elimination half-life and drug
concentration is shown:

• The elimination half-life is dependent on the Michaelis–Menten

parameters and concentration.

• Clinically, if the half-life is increasing as plasma concentration

increases,

• and there is no apparent change in metabolic or renal function,

• then there is a good possibility that the drug may be metabolized by

nonlinear kinetics.
Dependence of Clearance on Dose:
• The total body clearance of a drug (given by IV bolus injection that
follows a one-compartment model with Michaelis–Menten
elimination kinetics) changes with respect to time and plasma drug
concentration.

• Within a certain drug concentration range, an average or mean

clearance (Clav) may be determined.

• Because the drug follows Michaelis–Menten kinetics, Cl(av) is dose

dependent. Cl(av) may be estimated from the area under the curve
and the dose given.
• According to the Michaelis–Menten equation:
• Inverting above Equation and rearranging yields

• Integration of above Equation from time 0 to

infinity gives Equation

• Because the dose D0= Cp0/Vd Equation may be

expressed as
EXAMPLE:
• The clearance (apparent) of many of the drugs in patients who
are slow metabolizers changes with dose.

• Metoprolol and many b-adrenergic antagonists are extensively

metabolized.

• The plasma levels of metoprolol in slow metabolizers were much

greater than other patients, and the AUC, after equal doses, is
several times greater among slow metabolizers of metoprolol.
DRUGS DISTRIBUTED AS ONE-COMPARTMENT
MODEL AND ELIMINATED BY NONLINEAR
PHARMACOKINETICS:

1. Mixed Drug Elimination:

• the drug may be eliminated by both nonlinear (Michaelis Menten)
and linear(first-order) processes.

• Drugs may be metabolized to several different metabolites by

parallel pathways.

• At low drug doses corresponding to low drug concentrations at the

site of the biotransformation enzymes, the rates of formation of
metabolites are first order.
• However with higher doses of drug, more drug is absorbed and
higher drug concentrations are presented to the biotransformation
enzymes.
• At higher drug concentrations, the enzyme involved in metabolite
formation may become saturated, and the rate of metabolite
formation becomes nonlinear and approaches zero order.

• For example,
• sodium salicylate is metabolized to both a glucuronide and a glycine
conjugate (hippurate).
• The rate of formation of the glycine conjugate is limited by the
amount of glycine available.
• Thus, the rate of formation of the glucuronide continues as a first-
order process, whereas the rate of conjugation with glycine is
capacity limited.
• The equation that describes a drug that is eliminated by both first-
order and Michaelis–Menten kinetics after IV bolus injection is
given by:

• where
• k is the first-order rate constant representing the sum of all first-
order elimination processes,
• V’max is simply Vmax expressed as concentration by dividing by
VD.
2. Zero-Order Input and Nonlinear Elimination
• The usual example of zero-order input is constant IV infusion.

• If the drug is given by constant IV infusion and is eliminated only

by nonlinear pharmacokinetics, then the following equation
describes the rate of change of the plasma drug concentration:

• where k0 is the infusion rate

• and VD is the apparent volume of distribution.
3. First-order Absorption And Nonlinear Elimination
• The relationship that describes the rate of change in the plasma drug
concentration for a drug that is given extravascularly (eg, orally),
absorbed by firstorder absorption,

• and eliminated only by nonlinear pharmacokinetics, is given by the

following equation.

• CGI is concentration in the GI tract.

• where ka is the first-order absorption rate constant.

• If the drug is eliminated by parallel pathways consisting of both
linear and nonlinear pharmacokinetics, above Equation may be
extended to

• Where k is the first order elimination rate constant.

CHRONOPHARMACOKINETICS AND TIME-DEPENDENT
PHARMACOKINETICS
• CHRONOPHARMACOKINETICS:
broadly refers to a temporal change in the rate process (such as
absorption or elimination) of a drug.

• The temporal changes in drug absorption or elimination can be

cyclical over a constant period (eg, 24-hour interval),

• or they may be noncyclical, in which drug absorption or elimination

changes over a longer period of time.

• Chronopharmacokinetics is an important consideration during drug

therapy
• TIME-DEPENDENT PHARMACOKINETICS:
• generally refers to a noncyclical change in the drug absorption or
drug elimination rate process over a period of time.

• Time-dependent pharmacokinetics leads to nonlinear

pharmacokinetics.
• Time-dependent pharmacokinetics may be the result of alteration in
the physiology or biochemistry in an organ or a region in the body
that influences drug disposition.
• Time-dependent pharmacokinetics may be due to auto induction or
auto inhibition of biotransformation enzymes.

• For example, repeated doses of carbamazepine induce the enzymes

responsible for its elimination, thereby increasing the clearance of
the drug.
CIRCADIAN RHYTHMS AND INFLUENCE ON
DRUG RESPONSE:

• Circadian rhythms are rhythmic or cyclical changes in plasma drug

concentrations that may occur daily, due to normal changes in body
functions.

• They are controlled by genes and subject to modification by

environmental factors.

• Circadian rhythms are regulated through periodic activation by a set

of clock genes.
• For example, melatonin onset is associated with onset of the of
cortisol secretion period that regulates many functions

• Some well known circadian physiologic parameters are :

• Core body temperature (CBT),

• heart rate (HR),
• cardiovascular parameters
Clinical and Adverse Toxicity Due to Non-linear
Pharmacokinetics:
• The presence of nonlinear or dose-dependent pharmacokinetics,
due to saturation of a process involving absorption, first-pass
metabolism, binding, or renal excretion, can have significant
clinical consequences.

• However, nonlinear pharmacokinetics may not be noticed in drug

studies that use a narrow dose range in patients.

• In this case, dose estimation may result in disproportionate

increases in adverse reactions but insufficient therapeutic benefits.

• Nonlinear pharmacokinetics can occur anywhere above, within, or

below the therapeutic window