Nonlinear Pharmacokinetics

• INTRODUCTION
• Pharmacokinetic parameters,
(t1/2), (K), (V) and the (Cl) of most
drugs are not expected to change
when different doses are
administered and/or when the
drug is administered via different
routes as a single or multiple
doses.
• The kinetics of these drugs is described
as linear, or dose-independent
pharmacokinetics and is characterized
by the first-order process.
• The term linear simply means that
plasma concentration at a given time
at steady state and the area under the
plasma concentration versus time
curve (AUC) will both be directly
proportional to the dose administered.
• This does not apply for some
drugs. For example, when the
daily dose of phenytoin is
increased from 300mg to 450 mg,
the Cpss may increase by as much
as 10-fold.
• This dramatic increase is
attributed to the non-linear
kinetics of phenytoin.
• For drugs that exhibit non-linear
(dose dependent kinetics), the
fundamental pharmacokinetic
parameters may vary depending on
the administered dose.
• This is because one or more of the
kinetic processes (absorption,
distribution and/or elimination) may
be occurring via a saturable
• Nonlinearity arises when therapeutic
drug concentrations are high enough
to saturate an enzyme or another
protein involved in ADME.
• Consequently, nonlinear
pharmacokinetics has the potential to
arise whenever a protein is involved in
ADME.
• See below for processes in ADME that
involve proteins
• Some clinical examples of the saturation of
the processes include:
• reduced absorption of riboflavin at higher
doses
• reduced presystemic extraction of
propranolol with higher doses
• dose-dependent protein binding of valproic
acid
• saturable tissue uptake of methotrexate; and
• Saturation of phenytoin and ethanol
metabolism at higher doses.
• Nonlinearity can also arise from:
• 1- drugs such as carbamazepine that induce their
own metabolism will display nonlinear
pharmacokinetics until the induction process
stabilizes, which generally takes about 10–14 days.
• 2- pharmacological or toxicological actions of a drug
e.g. theophylline induces concentration-dependent
diuresis, resulting in increased renal excretion with
dose. Interestingly, this offsets by the drug’s
saturable metabolism leading to overall linear
pharmacokinetics of theophylline.
• 3-The clearance of aminoglycosides can decrease
with dose as a result of dose-dependent renal
toxicity.
• However, nonlinearity due to capacity-limited
metabolism is the most common example of
observed clinically, and this will be discussed further
during our lecture.
• MICHAELIS-MENTEN ENZYME KINETICS
• Enzymes usually react with the substrate
(drug) to form enzyme-substrate complexes;
then, the product (metabolite) is formed.
• The enzyme can go back to react with
another substrate to form another molecule
of the product.
• E + D ↔ ED → E + M
• where E is the enzyme, D is the drug, ED is
the drug-enzyme complex, and M is the
metabolite.
• According to the M-M kinetics, a
quantitative relationship between the
enzymatic reaction rate V and drug
concentration Cp may be expressed as:
• V = Vmax Cp/(Km+ Cp)
• where Vmax is the maximum rate of the
enzymatic reaction, and Km is the M-M
constant. Graphically, this relationship
can be presented as in the fig. below:
• The rate of metabolism, or the rate of
elimination (if metabolism is the only
pathway of elimination), is defined by the
Michaelis–Menten equation:
• Rate of drug metabolism = Vmax Cp/(Km+
Cp)
• where Vmax is the maximum rate of drug
metabolism, and Km is the drug
concentration when the rate of the drug
metabolism is half the maximum rate
• Km is inversely related to the affinity of the drug for
the metabolizing enzymes.
• This hyperbolic relationship indicates that, as the Cp
increases, the rate of drug metabolism increases
until it reaches a plateau at a high drug
concentrations.
• At this plateau, the enzyme system is saturated,
and the metabolic rate is at its maximum value.
• Theoretically, all metabolic pathways can be
saturated at a high drug concentration. However,
saturable drug metabolism is of great clinical
significance when saturation occurs after
therapeutic doses.
• Referring to the relationship above, at low drug
concentration (i.e., Km >> Cp), the equation (Rate =
Vmax Cp/(Km+ Cp)) is reduced to: Rate ≈ (VmaxCp / Km)
• This means that the reaction rate becomes
proportional to the drug concentration, and the
metabolic process follows first-order kinetics.
• However, at a high drug concentration (i.e. Km < <
Cp) the equation is reduced to:
• Rate ≈ (Vmax Cp/Cp) ≈ Vmax
• This means the reaction rate becomes constant and
independent of the drug concentration and follows
zero-order kinetics.
• PHARMACOKINETIC PARAMETERS
• The Vmax of a metabolic pathway is the maximum
rate of drug metabolism through this particular
pathway.
• Vmax is dependent on the amount of enzyme
molecules involved in the metabolic process.
• Conditions like enzyme induction increase the
available amount of the enzymes and can increase
Vmax .
• Enzyme induction increases the amount of the
enzyme without affecting its affinity to react with
drugs, i.e. It does not affect the Km. See below
• The M-M constant Km is a qualitative characteristic
of how an enzyme interacts with the drugs and is
independent of the enzyme concentration.
• In the presence of a competitive inhibitor of the
enzyme, the metabolic rate will be slower at any
given drug concentration.
• However, as the drug concentration increases
relative to the inhibitor concentration, the
maximum metabolic rate will be achieved.
• This means that, in the presence of a competitive
inhibitor, Km will increase without affecting Vmax as
seen below.
• A CP-TIME PROFILE AFTER A SINGLE IV DOSE OF A
DRUG ELIMINATED THROUGH M-M KINETICS
• The model below describes the drug
pharmacokinetic behavior after a single (IV) dose
when the drug elimination is through a single
metabolic pathway that follows M-M kinetics.
• The Cp - time profile of this drug will be:
• The rate of decline in the amount of the drug in the
body is:
• -dA/dt = Vmax Cp/(Km + Cp)
• Integration of the equation above and division by
the volume of distribution gives:
• Cp = Cp0 + Km ln(Cp0 / Cp) – Vmax t/Vd

• This equation cannot be used to calculate the Cp at

specific times because the term Cp is present in
both sides of the equation and cannot be
separated.
• After Multiple Drug Administrations
• The rate of drug administration is equal to the rate
of drug elimination at steady state. When the drug
is eliminated by a single metabolic pathway that
follows M-M kinetics, the relationship between the
dosing rate and steady-state drug plasma
concentration can be described by the following
equation:
• F D/T = Vmax Cpss /(Km + Cpss)
• This relationship can be rearranged to obtain an
expression for the steady-state drug plasma
concentration:
• Cpss = (DF/T) Km /[Vmax – (DF/T)]
• This means that, increasing doses of the drug result
in more than proportional increase in the steady-
state plasma drug concentration.
• Leih teftakir?
• In the eq. (Cpss =(DF/T) Km /[Vmax –(DF/T)] if the
dosing rate (D/T) exceeds Vmax the calculated Cpss will
be a negative value.
• The Cpss cannot be a negative value. But from the
definition of Vmax it is the maximum rate of drug
elimination. So, if the dosing rate exceeds Vmax then
steady state will never be achieved, and continuous
accumulation of the drug in the body will occur.
• DETERMINATION OF THE PHARMACOKINETIC
PARAMETERS
• TOTAL BODY CLEARANCE
• The total body clearance can be determined by:
• CLT = Vmax /(Km + Cp)
• As the Cp becomes higher, the CLT will become
lower.
• HALF-LIFE
• t1/2 = [0.693 Vd/Vmax](Km + Cp)
• The t1/2 is longer when the drug concentration is
higher.
• The CLT and the t1/2 are different at different drug
concentrations.
• After a single drug administration, the Cp will be
changing, and the CLT and t1/2 will be changing.
• However, at steady state the Cp will be fluctuating
around an average Cpss, and ,the CLT and t1/2 can
be estimated at this average steady-state
concentration.
• EFFECT OF CHANGING THE PHARMACOKINETIC
PARAMETERS ON PLASMA CONCENTRATION-TIME
PROFILE
• Dose
• Administration of larger doses achieves higher initial
Cps resulting in lower CLT and longer t1/2.
• However, at any concentration the rate of decline of
the drug concentration is similar because K m and Vmax
are constant.
• Increasing the dose results in more than a
proportional increase in the Cpss during multiple drug
administrations.
• It takes a longer time to achieve steady state following
• Vmax
• A larger Vmax results in higher CLT and shorter t1/2,
which lead to a faster rate of drug elimination and
AUC.
• Following multiple administrations of similar doses,
the Cpss will be lower when Vmax is higher.
• Km
• A larger Km results in lower CLT and longer t1/2,
which lead to a slower rate of drug elimination and
larger AUC.
• Following multiple administrations of similar doses,
the Cpss will be higher when Km is higher.
• ORAL MINISTRATION OF DRUGS ELIMINATED BY
M-M PROCESS
• The rate of drug absorption significantly affects the
Cp-time profile after a single oral dose.
• After the same dose, rapidly absorbed formulations
will achieve higher Cps (larger AUCs) compared to
slowly absorbed formulations. Keif?
• During multiple drug administration, the Cpss is
dependent on the dose, Vmax and Km.
• Example 1
• A patient is to begin taking phenytoin. A Cpss of
15mg/L is desired. Assuming a Vmax of 400mg/day
and a Km value of 4 mg/L, what rate of
administration of phenytoin sodium (S = 0.92 and F
= 1) should be used?
• Solution
• Use the equation:

• 0.9X1XD/T = 400X15/(15+4)
• D/T = 343mg/day
• Example 2
• A patient’s individual Vmax and Km values are found
to be 450 mg/day and 5mg/L, respectively. What
are her/his estimated Cpss values from doses of:
• (a) 350mg/day
• (b) 400mg/day, and
• (c) 450 mg/day?
• Solution
• Use the equation:

• a. Cpss = 5X350X0.92/[450-(350X0.92)] = 12.6mg/L

• Using the same method:
• b. = 22.4mg/L
• c. = 57.5mg/L
• Influence of Km and Vmax and Factors That Affect
These Parameters
• For drugs that display nonlinear pharmacokinetics,
the relationship between dose and the Cpss is
controlled by Vmax and Km.
• It is important to understand the role that each
parameter plays in the dose–Cp relationship.
• Additionally, it is important to be aware of any
situations where either of the parameters may
differ from normal and to know how to plan therapy
in the light of any known or suspected changes.
• See below for some factors that can affect
phenytoin’s Vmax and Km.
• Time to Eliminate the Drug
• When elimination is not a first-order process, the
concept of a half-life does not hold and there is no
simple way to estimate the time it takes for the
plasma concentration to fall by 50% or any other
amount.
• If there is no ongoing drug input, the drug in the body is only
under the influence of elimination:

• where Cp0 is the plasma concentration at t = 0, and Cpt is the

• Example 3
• A patient (Vd = 45 L, Vmax = 400 mg/day, and Km =
4 mg/L) presents with a phenytoin concentration of
40 mg/L.
• (a) How long will it take for the plasma
concentration to reach the therapeutic range (20
mg/L)?
• (b) How long will it take for plasma concentrations
to fall another 50%, to 10 mg/L?
• Solution
• Using the equation:

• a. t = 45/400[40-20+4ln(40/20)] = 2.56days

• b. t = 45/400[20-10+4ln(20/10)] = 1.44days
• Time to Reach Steady State
• Once again, there is no simple way to estimate the
time it takes to reach steady state.
• An expression for the time it takes to get to 90%
steady state (t90%) is obtained using the equation:
• Example 4
• The population average parameters for phenytoin in
a standard 70-kg male are: Vd = 45.5 L, Vmax =
400mg/day, and Km = 6 mg/L. How long will it take
to get to 90% steady state when the dose is
administered at a rate of 300mg of phenytoin
sodium per day?
• Solution
• Using the equation:

• Calculate the same using 250 and 350 doses

• Individualization of Doses of Phenytoin
• When starting phenytoin therapy, the wide
interindividual variability in Vmax and Km, and
phenytoin’s narrow therapeutic range, makes it
essential to monitor the Cps and individualize the
dose if necessary.
• Patients are first evaluated for factors that warrant
different dosing, e.g.
• Concomitant medications.
• The presence of liver disease.
• The presence of renal disease.
• If none of the above factors are present, the patient
may be started on a standard dose of about
7mg/kg/day of phenytoin sodium.
• Once steady state has been achieved, after about 2
weeks, the phenytoin concentration can be
evaluated.
• If the plasma concentration is in the therapeutic
range, the dose will be maintained.
• If not, the dose is modified based on the patient’s
history with the drug: i.e. the Cpss achieved by the
initial rate of drug administration (one S ⋅ F ⋅Ra -
Cpss data pair).
• Modification of Dose Based on One Data Pair
• The process of individualization involves estimating
the patient’s individual pharmacokinetic parameters
for phenytoin.
• Let us recall the basic formula that relates the rate
of drug administration to the steady-state plasma
concentration:

• The relationship between Cpss and S ⋅ F ⋅ Ra is

controlled by Vmax and Km.
• With only one Cpss–S ⋅ F ⋅ R data pair, it is possible
to estimate only one of phenytoin’s pharmacokinetic
parameters.
• Since it is critical that the drug is not administered
at a rate that exceeds Vmax, this is usually
estimated first.
• The population average value of Km (4 mg/L) is
assumed for the patient.
• Then use the arrangement of the basic equation
that solves for Vmax:
• The initial rate of drug administration (S ⋅ F ⋅ Ra)
and the steady-state concentration it achieved are
substituted in the equation along with the
population average Km of 4mg/L, and Vmax is
estimated.
• The Vmax calculated, the population average Km (4
mg/L), and the steady-state plasma concentration
desired (usually 15 mg/L) are then substituted into
the arrangement of the basic equation that solves
for S ⋅ F ⋅ Ra:
• Example 5
• A patient has been taking Dilantin 300 mg daily for 2
weeks. At this time, a plasma sample reveals a
phenytoin concentration of 8mg/L. Recommend a
new dose to achieve a steady-state concentration of
15 mg/L.
• Solution
• The population average Km (4 mg/L) will be
assumed. Then to estimate the patient’s Vmax we
use the equation:

• Vmax = 0.92X300X(8+4)/8 = 414mg/day

• This Vmax value and the population average Km are
now used to estimate a rate of administration to
provide the desired Cpss of 15 mg/L:
• The new rate of drug administration may also be
assessed about 2 weeks later when a new steady
state would be expected.
• If this steady-state plasma concentration is not
satisfactory, a new rate of drug administration must
be determined.
• If this is the case, two S ⋅ F ⋅ Ra–Cpss data pairs are
now available. These can be used to estimate both
the Vmax and Km values of the patient.
• Modification of Dose Based on Two Data Pairs
• The values of Km and Vmax are estimated from two
or more data pairs as illustrated below:
• Taking the basic equation that is expressed in terms
of:

• Rearranging gives us

• Rearranging again, we obtain

• A plot of S ⋅ F ⋅ Ra against S ⋅ F ⋅ Ra/Cpss yields a
straight line of slope -Km and intercept Vmax (as
seen below).
• If more than two data pairs are available, a full plot
can be constructed.
• If only two data pairs are available, they are simply
used to calculate the slope of the line S ⋅ F ⋅ Ra
against S ⋅ F ⋅ Ra/Cpss.
• This provides a value for Km. The estimate of Vmax
can be obtained using equation:
• Example 6
• Continuing with example 5, recall that an initial
dose of 300 mg/day phenytoin sodium provided a
steady-state plasma concentration of 8 mg/L. The
dose was increased to 350 mg/day. Two weeks later,
the second dose was found to provide a steady
state plasma concentration of 11mg/L. Recommend
a dose to provide a steady-state plasma
concentration of 15 mg/L.
• Solution
• The existing history on this patient can be
summarized as follows:
• The first rate of drug administration is Ra1(300
mg/day) gave a Cpss1 value of 8 mg/L and the
second rate of drug administration is Ra2(350
mg/day) gave a Cpss2 value of 11 mg/L.
• The patient’s Km value is estimated first using
equation:

• Km = 350-300/[(300/8)-(350/11)] = 8.8mg/L
• Vmax is calculated, using equation using (either
data pair) as:
• Vmax = 0.92 × 300 × (8.8 + 8)/8 = 579.6 mg/day

• The new dose is then calculated using equation:

• S ⋅ F ⋅ Ra = 579.6 × 15/15X8.8 = 365

• Ra = 365/0.92 = 397 mg/day
• i.e. About 400mg/day
• PROBLEMS
• 1. C.R. is a 45-year-old 85-kg male (height 180 cm),
who experiences simple partial seizures. He has
normal liver and renal function and is not taking any
other medications. He has started taking 400mg of
extended release phenytoin sodium daily. Two
weeks later, a plasma concentration, which is
assumed to be steady state, is found to be 6.6 mg/L.
The patient says that he has taken all the doses as
directed. Suggest a dosage regimen to achieve a
steady-state phenytoin concentration of 15 mg/L.
• 2. L.M. is a 29-year-old female who has been taking
carbamazepine for 7 months to control her epilepsy.
She still experiences several seizures each month. It
is decided to discontinue carbamazepine and try
phenytoin. She is prescribed dilantin (300 mg b.i.d.).
Three weeks later, she says that she has not
experienced a seizure and feels great. However,
about 1 month later, she returns to the physician
and complains of feeling unsteady and having
difficulty keeping focused on activities. A blood
sample is taken and the phenytoin plasma
concentration is found to be 28 mg/L. Suggest
possible explanations for these observations and
recommend a more appropriate dose of phenytoin.
• 3. A patient who is suspected to have reduced
intrinsic clearance of phenytoin is started on a dose
of 250 mg of phenytoin sodium daily.
• (a) Two weeks after the start of therapy, a steady-
state plasma concentration is found to be 4 mg/L.
Estimate her Vmax and recommend a new dose.
• (b) Her dose is increased to 400 mg of phenytoin
sodium daily. Two weeks later, a steady-state
plasma concentration is found to be 10 mg/L.
Determine her Km and Vmax values and
recommend a new dose.