NONLINEAR

PHARMACOKINETICS
Course Title : Biopharmaceutics and
Pharmacokinetics – II
 DEFINITION

• Nonlinear pharmacokinetics may be defined

as dose dependent pharmacokinetics.
• As the dose of the drug changes, the
pharmacokinetic parameters also changes.
 INTRODUCTION
• Linear pharmacokinetic models using simple
first-order kinetics were introduced to
describe the course of drug disposition and
action.
• These linear models assumed that the
pharmacokinetic parameters for a drug would
not change when different doses or multiple
doses of a drug were given.
• 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.
• Many of the processes of drug absorption,
distribution, biotransformation, and excretion
involve enzymes or carrier-mediated systems.
• For some drugs given at therapeutic levels,
one of these specialized processes may
become saturated.
• Various causes of nonlinear pharmacokinetic
behavior are theoretically possible.
Causes of nonlinear pharmacokinetics :
• saturation of plasma protein-binding or
carrier-mediated systems,
• Due to a pathologic alteration in drug
absorption, distribution, and elimination. For
example, aminoglycosides may cause renal
nephrotoxicity, thereby altering renal drug
excretion. In addition, gallstone obstruction of
the bile duct will alter biliary drug excretion.
• In most cases, the main pharmacokinetic
outcome is a change in the apparent
elimination rate constant.
 Examples of Drugs Showing Nonlinear
Kinetics

CAUSE DRUG
GI Absorption

Saturable transport in gut wall Riboflavin, gebapentin, L-dopa, baclofen,

ceftibuten
Intestinal metabolism Salicylamide, propranolol

Drugs with low solubility in GI but Chorothiazide, griseofulvin, danazol

relatively high dose
Saturable gastric or GI decomposition Penicillin G, omeprazole, saquinavir
 Examples of Drugs Showing Nonlinear
Kinetics

CAUSE DRUG
Distribution

Saturable plasma protein binding Phenylbutazone, lidocaine, salicylic acid,

ceftriaxone
Cellular uptake Methicillin (rabbit)

Tissue binding Imiprimine (rat)

CSF transport Benzylpenicillins

Saturable transport into or out of tissues Methotrexate

 Examples of Drugs Showing Nonlinear
Kinetics

CAUSE DRUG

Renal Elimination

Active secretion Mezlocillin, para-aminohippuric acid

Tubular reabsorption Riboflavin, ascorbic acid, cephapirin

Change in urine pH Salicylic acid, dextroamphetamine

 Examples of Drugs Showing Nonlinear
Kinetics
CAUSE DRUG

Metabolism

Saturable metabolism Phenytoin, salicyclic acid, theophylline,

valproic acid
Cofactor or enzyme limitation Acetaminophen, alcohol

Enzyme induction Carbamazepine

Altered hepatic blood flow Propranolol, verapamil

Metabolite inhibition Diazepam

 Examples of Drugs Showing Nonlinear
Kinetics

CAUSE DRUG

Biliary Excretion

Biliary secretion Iodipamide, sulfobromophthalein sodium

Enterohepatic recycling Cimetidine, isotretinoin

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.
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 (i.e,
competition effects).
5. The composition and/or ratio of the
metabolites of a drug may be affected by a
change in the dose.
• Because these drugs have a changing apparent
elimination constant with larger doses,
prediction of drug concentration in the blood
based on a single small dose is difficult.
• Drug concentrations in the blood can increase
rapidly once an elimination process is saturated.
In general, metabolism (biotransformation) and
active tubular secretion of drugs by the kidney
are the processes most usually saturated.
• The following figure shows plasma level–time
curves for a drug that exhibits saturable kinetics.
 Figure 1: Plasma level–time curves for a
drug that exhibits a saturable elimination
process
• 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).
• If the pharmacokinetic data were estimated only
from the blood levels described by curve B, then
a twofold increase in the dose would give the
blood profile presented in curve C, which
considerably underestimates the drug
concentration as well as the duration of action.
• 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 (Figure 2).
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.
 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
Michaelis–Menten kinetics Graph
Saturable Enzymatic Elimination
Processes
 Calculate Time from Amount
If we want to know the time required for a
certain amount of drug to decrease, then the
equation would be :

𝟏 𝑫𝟎
𝒕= 𝑫𝟎 − 𝑫𝒕 + 𝑲𝑴 𝒍𝒏
𝑽𝒎𝒂𝒙 𝑫𝒕
• where V max is the maximum elimination rate and
K M is the Michaelis constant that reflects the
capacity of the enzyme system.
• It is important to note that K M 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 0.5V max.
• The values for K M and V max are dependent on the
nature of the drug and the enzymatic process
involved.
• The elimination rate of a hypothetical drug with a
K M of 0.1 g/mL and a V max of 0.5 g/mL per hour
is calculated in by means of the above equation.
• Because the ratio of the elimination rate to drug
concentration changes as the drug concentration
changes (ie, dC p/dt is not constant, above
Equation), the rate of drug elimination also
changes and is not a first-order or linear process.
• In contrast, a first-order elimination process
would yield the same elimination rate constant at
all plasma drug concentrations.
• At drug concentrations of 0.4–10 g/mL, the
enzyme system is not saturated and the rate
of elimination is a mixed or nonlinear process
(table 9-2).
• At higher drug concentrations, 11.2 g/mL and
above, the elimination rate approaches the
maximum velocity (V max) of approximately 0.5
g/mL per hour.
• At V max, the elimination rate is a constant and
is considered a zero-order process.
• The above equation describes a nonlinear
enzyme process that encompasses a broad
range of drug concentrations.
• 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 the Equation becomes:
 Question
Q. Using the hypothetical drug considered in (V
max = 0.5 g/mL per hour, K M = 0.1 g/mL), how
long would it take for the plasma drug
concentration to decrease from 20 to 12 g/mL?
Solution
• Because 12 g/mL is above the saturable level,
as indicated in , elimination occurs at a zero-
order rate of approximately 0.5 g/mL per hour.
• A saturable process can also exhibit linear
elimination when drug concentrations are
much less than enzyme concentrations.
• When the drug concentration C p is small in
relation to the K M, the rate of drug
elimination becomes a first-order process.
• The data generated from Equation 9.2 (C p
0.05 g/mL, ) using K M = 0.8 g/mL and V max =
0.9 g/mL per hour shows that enzymatic drug
elimination can change from a nonlinear to a
linear process over a restricted concentration
range.
• This is evident because the rate constant (or
elimination rate/drug concentration) values
are constant.
• At drug concentrations below 0.05 g/mL, the
ratio of elimination rate to drug concentration
has a constant value of 1.1 hr– 1.
• Mathematically, when C p is much smaller
than K M, C p in the denominator is negligible
and the elimination rate becomes first order.
• When given in therapeutic doses, most drugs
produce plasma drug concentrations well
below K M for all carrier-mediated enzyme
systems affecting the pharmacokinetics of the
drug.
• Therefore, most drugs at normal therapeutic
concentrations follow first-order rate
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.
 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 in Equation
9.16.
• The elimination half-life is dependent on the
Michaelis–Menten parameters and
concentration.
• Some pharmacokineticists prefer not to
calculate the elimination half-life of a
nonlinear drug because the elimination half-
life is not constant.
• 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.
 Chronopharmacokinetics
• 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
(e.g., 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
• 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.
• Unlike dose-dependent pharmacokinetics, which
involves a change in the rate process when the
dose is changed, 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, studies have shown that
repeated doses of carbamazepine induce the
enzymes responsible for its elimination (ie,
auto-induction), thereby increasing the
clearance of the drug.
• Auto-inhibition may occur during the course
of metabolism of certain drugs.
• In this case, the metabolites formed increase
in concentration and further inhibit
metabolism of the parent drug.
• In biochemistry, this phenomenon is known as
product inhibition. Drugs undergoing time-
dependent pharmacokinetic have variable
clearance and elimination half-lives.
• The steady-state concentration of a drug that
causes auto-induction may be due to
increased clearance over time.
• Some anticancer drugs are better tolerated at
certain times of the day; for example, the
antimetabolite drug, fluorouracil (FU) was least
toxic when given in the morning to rodents.
• A list of drugs that demonstrate time dependence
is shown in next slide.
• In pharmacokinetics, it is important to recognize
that many isozymes (CYPs) are involved in drug
metabolisms.
• A drug may competitively influence the
metabolism of another drug within the same CYP
subfamily.
• Sometimes, an unrecognized effect from the
presence of another drug may be misjudged as
time-dependent pharmacokinetics.
 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.
• Some rhythmic changes that influence body
functions and drug response are controlled by
genes and subject to modification by
environmental factors.
 Circadian Rhythms and Influence on
Drug Response

• The mammalian circadian clock is a self-

sustaining oscillator, usually within a period of
~24 hours, that cyclically controls many
physiological and behavioral systems.
• The biological clock attempts to synchronize
and respond to changes in length of the
daylight cycle and optimize body functions.
• Circadian rhythms are regulated through
periodic activation of transcription by a set of
clock genes.
• For example, melatonin onset is associated
with onset of the quiescent period of cortisol
secretion that regulates many functions.
• Some well-known circadian physiologic
parameters are core body temperature (CBT),
heart rate (HR), and other cardiovascular
parameters.
• These fundamental physiologic factors can affect
disease states, as well as toxicity and therapeutic
response to drug therapy.
• The toxic dose of a drug may vary as much as
several-fold, depending on the time of drug
administration—during either sleep or wake
cycle.
• For example, the effects of aminoglycoside
administration timing on serum aminoglycoside
levels and the incidence of nephrotoxicity were
studied in 221 patients
• Each patient received an IV injection of 2–4
mg/kg gentamicin or tobramycin once daily at: (1)
between midnight and 7:30 AM, (2) between 8
AM and 3:30 PM, or (3) between 4 PM and 11:30
PM.
• In this study, no statistically significant differences
in drug trough levels (0–4.2 mg/L) or peak drug
levels (3.6–26.8 mg/L) were found for the three
time periods of drug administration.
• However, nephrotoxicity occurred significantly
more frequently when the aminoglycosides were
given during the rest period (midnight to 7:30
AM).
• Many factors contribute to nephrotoxicity
were discussed; the time of administration
was considered to be an independent risk
factor in the multivariate statistical analysis.
• Time-dependent
pharmacokinetics/pharmacodynamics are
important, although it is not always possible
to detect the difference in drug concentration
clinically because of multivariates.
 QUESTION
• What is the cause of nonlinear pharmacokinetics that is not
dose related?
Ans: Chronopharmacokinetics is the main cause of nonlinear
pharmacokinetics that is not dose related. The time
dependent or temporal process of drug elimination can be the
result of rhythmic changes in the body. For example,
nortriptyline and theophylline levels are higher when
administered between 7 and 9 AM compared to between 7
and 9 PM after the same dose. Biological rhythmic differences
in clearance cause a lower elimination rate in the morning
compared to the evening. Other factors that cause nonlinear
pharmacokinetics may result from enzyme induction (eg,
carbamazepine) or enzyme inhibition after multiple doses of
the drug. Furthermore, the drug or a metabolite may
accumulate following multiple dosing and affect the
metabolism or renal elimination of the drug.
 QUESTION

• Distinguish between linear and nonlinear

pharmacokinetics.
 REFERENCE
• Applied Biopharmaceutics and
Pharmacokinetics – Leon Shargel, Sussana
Wu-Pong, Andrew B.C. Yu, 6th Edition, Mc
Graw Hill Inc.
Chapter -9