15

Nonlinear pharmacokinetics

15.1 Introduction 323 15.5 Time to reach a given fraction of steady 332
state
15.2 Capacity-limited metabolism 325
15.6 Example: calculation of parameters for 333
15.3 Estimation of MichaelisMenten 327 phenytoin
parameters (Vmax and Km )
15.4 Relationship between the area under 330
the plasma concentration versus time
curve and the administered dose

Objectives
Upon completion of this chapter, you will have the ability to:
perform pharmacokinetic calculations for drugs that have partially saturated their metabolic sites
(capacity-limited metabolism)
obtain values of the MichaelisMenten elimination parameters from plasma drug concentration
data, either graphically or by equation
estimate the daily dosing rate necessary to attain a target steady-state plasma drug concentration
calculate the steady-state plasma drug concentration that will be attained from a given daily dosing
rate
estimate the time necessary to reach 90% of steady-state plasma drug concentrations
calculate target phenytoin concentrations for a patient with hypoalbuminemia.

15.1 Introduction
Pharmacokinetic parameters, such as elimination half
life (t1/2 ), the elimination rate constant (K), the appar-
ent volume of distribution (V), and the systemic clear-
ance (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
dose or multiple doses. The kinetics of these drugs is
described as linear, or dose-independent, pharmacoki-
netics and is characterized by the first-order process.
The term linear simply means that plasma concen-
tration 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, as illustrated in Fig. 15.1.
For some drugs, however, the above situation may
not apply. For example, when the daily dose of pheny-
toin is increased by 50% in a patient from 300 mg to
450 mg, the average steady-state plasma concentra-
tion, (Cp )ss , may increase by as much as 10-fold. This
dramatic increase in the concentration (greater than
324 Basic Pharmacokinetics

(a) 100 (b) 100

90 90
80 80

AUC (mg h1 L1)

70 70
(Cp)ss (mg L-1)

60 60
50 50
40 40
30 30
20 20
10 10
0 0
0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100
Dose (mg) Dose (mg)

Figure 15.1 Relationship between the plasma concentration (Cp ) at a given time at steady state (a) and the area under the
plasma concentration versus time curve (AUC) (b) against the administered dose for a drug that exhibits dose-independent
pharmacokinetics.

directly proportional) is attributed to the nonlinear Furthermore, administration of different doses of

kinetics of phenytoin. these drugs may not result in parallel plasma concen-
For drugs that exhibit nonlinear or dose- tration versus time profiles expected for drugs with
dependent kinetics, the fundamental pharmacokinetic linear pharmacokinetics (Fig. 15.3).
parameters such as clearance, the apparent volume For drugs with nonlinear metabolism, the initial
rate of decline in the plasma concentrations of high
of distribution, and the elimination half life may vary
doses of drug may be less than proportional to the
depending on the administered dose. This is because
plasma concentration; by comparison, after the ad-
one or more of the kinetic processes (absorption, dis-
ministration of lower doses, the rate of decline will
tribution and/or elimination) of the drug may be oc-
be proportional to plasma concentration and the pro-
curring via a mechanism other than simple first-order portionality constant will be K (Fig. 15.4).
kinetics. For these drugs, therefore, the relationship This means that the rate of elimination is not
between the AUC or the plasma concentration at a directly proportional to the plasma concentration for
given time at steady state and the administered dose these drugs. The reason for this nonlinearity is ex-
is not linear (Fig. 15.2). plained as follows:

(a) 70 (b) 1600

1400
60
1200
50
AUC (mg h1 L1)

1000
(Cp)ss (mg L-1)

40
800
30
600
20 400
10 200
0 0

0 200 400 600 800 1000 1200 0 200 400 600 800 1000 1200
Dose (mg) Dose (mg)

Figure 15.2 Relationship between the plasma concentration (Cp ) at a given time at steady state (a) and the area under the
plasma concentration versus time curve (AUC) (b) against the administered dose for a drug that exhibits dose-dependent
pharmacokinetics.
 Nonlinear pharmacokinetics 325

been shown that the antibacterial agent dicloxacillin

100
has saturable active secretion in the kidneys, result-
10 ing in a decrease in renal clearance as dose is in-
creased. Both phenytoin and ethanol have saturable
Cp (mg L-1)

1
metabolism, which means that an increase in dose
0.1 results in a decrease in hepatic clearance and a more
than proportional increase in AUC. In the remainder
0.01
of this chapter, nonlinearity in metabolism, which is
0.001 one of the most common sources of nonlinearity, will
0 20 40 60 80 100 120 140 160 be discussed.
Time (h)

Figure 15.3 The relationship between plasma

concentration (Cp ) and time following the administration of
different doses of a drug that exhibits dose-dependent
elimination pharmacokinetics.
0.10
15.2 Capacity-limited metabolism
Capacity-limited metabolism is also called saturable
metabolism, MichaelisMenten kinetics, or mixed-
order kinetics. The process of enzymatic metabolism
of drugs may be explained by the relationship
depicted below

0.08 Enzyme + Substrate (drug) Enzymedrug

Elimination rate/Cp

complex Enzyme + Metabolite.

0.06

First the drug interacts with the enzyme to produce

0.04
0.02
0.00
0 50 100 150
Time (h)
Figure 15.4 Plot of elimination rate (dCp /dt) normalized for
plasma drug concentration (Cp ) versus time. Early after a dose
of drug, when drug levels are high, dose-dependent
elimination kinetics may apply. In this case, the elimination
rate is less than proportional to plasma drug concentration.
When plasma drug levels have declined sufficiently (after
about 125 h in this figure), the elimination rate is directly
proportional to Cp , with proportionality constant K
(horizontal section).
Nonlinearity may arise at any one of the var-
ious pharmacokinetic steps, such as absorption,
distribution and/or elimination. For example, the
extent of absorption of amoxicillin decreases with
an increase in dose. For distribution, plasma protein
binding of disopyramide is saturable at the thera-
peutic concentration, resulting in an increase in the
volume of distribution with an increase in dose of
the drug. As for nonlinearity in renal excretion, it has
a drugenzyme intermediate. Then the intermediate
complex is further processed to produce a metabolite,
with release of the enzyme. The released enzyme is
recycled back to react with more drug molecules.
200 250 300
According to the principles of MichaelisMenten
kinetics, the rate of drug metabolism changes as
a function of drug concentration, as illustrated in
Fig. 15.5.
Based on this relationship, at very low drug con-
centration, the concentration of available enzymes is
much greater than the number of drug molecules or
the drug concentration. Therefore, when the concen-
tration of drug is increased, going from left to right
in Fig. 15.5, the rate of metabolism is also increased
proportionally (linear elimination kinetics). However,
after a certain point, as the drug plasma concentra-
tion increases, the rate of metabolism increases less
than proportionally. The other extreme occurs when
the concentration of drug is very high relative to the
concentration of available enzyme molecules. Under
this condition, all of the enzyme molecules are satu-
rated with the drug molecules and, when concentra-
tion is increased further, there will be no change in
the rate of metabolism of the drug. In other words,
the maximum rate of metabolism (Vmax ) has been
achieved.
326 Basic Pharmacokinetics

Elimination rate as fraction of Vmax

Zero-order region

MichaelisMenten region

0.5

First-order (linear) region

0
Drug concentration or mass of drug in body

Figure 15.5 Relationship between elimination rate and the plasma concentration of a drug that exhibits dose-dependent
pharmacokinetics. At high drug concentrations, where saturation occurs, the elimination rate approaches its maximum, Vmax .

The rate of metabolism, or the rate of elimination denominator of Eq. (15.1), yielding
if metabolism is the only pathway of elimination, is
Vmax C
defined by the MichaelisMenten equation: Metabolism rate = . (15.2)
Km
Vmax C Because both Vmax and Km are constants, the
Metabolism rate = (15.1)
Km + C metabolism rate is proportional to the drug concen-
tration and a constant (i.e., first-order process) in this
where Vmax is the maximum rate (mg h1 ) of region:
metabolism; Km is the MichaelisMenten constant
(mg L1 ), and C is the drug concentration (mg L1 ). Metabolism rate = KC (15.3)
The maximum rate of metabolism (i.e., Vmax ) is
where
dependent on the amount or concentration of en-
zyme available for metabolism of the drug; Km is the Vmax
K=
concentration of the drug that results in a metabolic Km
rate equal to one half of Vmax (Vmax /2). In addition, and where the units of K are
Km is inversely related to the affinity of the drug for
the metabolizing enzymes (the higher the affinity, the mg L1 h1
= h1 .
lower the Km value). mg L1
The unit for the maximum rate of metabolism is Equation (15.3) is analogous to the classical
the unit of elimination rate and is normally expressed first-order rate equation (dX/dt = KX).
as amount per unit time (e.g., mg h1 ). However, in At the other extreme, the drug concentrations are
some instances, it may be expressed as concentration much higher than Km ; therefore, the term Km may be
per unit time (e.g., mg L1 h1 ). deleted from the denominator of Eq. (15.1):
Equation (15.1) describes the relationship be-
tween the metabolism (or elimination) rate and the Vmax C
Metabolism rate = = Vmax . (15.4)
concentration over the entire range of concentrations. C
However, different regions of the MichaelisMenten Equation (15.4) is analogous to the zero-order equa-
curve (Fig. 15.5) can be examined with regard to tion (dX/dt = K0 ). Equation (15.4) shows that,
drug concentrations. At one extreme, the drug con- when the drug concentration is much higher than Km ,
centration may be much smaller than Km . In this the rate of metabolism is a constant (Vmax ), regard-
case, the concentration term may be deleted from the less of drug concentration. This situation is similar to
 Nonlinear pharmacokinetics 327

zero-order kinetics; at drug concentrations around the sured at various times. This gives a set of concentra-
Km , a mixed order is observed, which is defined by the tion versus time data (Fig. 15.6).
MichaelisMenten equation (Eq. 15.1). Use concentration versus time data and follow the
following steps to obtain the information necessary to
determine Vmax and Km .
15.3 Estimation of Determine dCp /dt (rate; units of mg L1 h1 ): for
MichaelisMenten parameters example,
(Vmax and Km ) (Cp )0 (Cp )1 1Cp
= .
Estimation of MichaelisMenten t1 t0 1t
parameters from administration of a Determine the midpoint concentration (i.e., average
single dose concentration; units of mg L1 ):
Following the administration of a drug as an intra- (Cp )0 + (Cp )1
venous solution, drug plasma concentration is mea- .
2

(a) 40

30
Zero-order region First-order
MichaelisMenten
Cp (mg L1)

region
region
20

10

0
0 15 30 45 60 75 90 105 120 135 150
Time (h)

(b) Zero-order region

100
MichaelisMenten
region

10 First-order
region
Cp (mg L1)

0.1

0.01
0 15 30 45 60 75 90 105 120 135 150
Time (h)

Figure 15.6 Plasma concentration (Cp ) versus time profile following the administration of an intravenous bolus dose of a drug
that exhibits the characteristics of dose-dependent pharmacokinetics. (a) Rectilinear plot; (b) semilogarithmic plot.
328 Basic Pharmacokinetics

The practical expression of the Michaelis A second way of linearizing Eq. (15.6)
Menten equation becomes:
!
1 Km 1 1
 = + .
 
1Cp Vmax (Cp )t 
1Cp
= . (15.5) Vmax (Cp )t Vmax
1t t Km + (Cp )t 1t t

There are two ways to linearize Eq. (15.5), which Each side of Eq. (15.6) is multiplied by (Cp )t :
will then enable determination of Vmax and Km .
(Cp )t Km (Cp )t
  = + . (15.7)
1Cp Vmax Vmax
LineweaverBurke plot 1t t
Take the reciprocal of Eq. (15.5) 
1Cp

The plot of (Cp )t / 1t versus (Cp )t will yield a
t
! straight line (Fig. 15.8).
1 Km 1 1
  = + . (15.6) The slope of this line is found as before, (Y2
1Cp Vmax (Cp )t Vmax
1t t Y1 )/(X2 X1 ), and will have units of (h)/(mg L1 ) =
  h L mg1 . The slope is 1/Vmax . So
1Cp
The plot of 1/ 1t against 1/(Cp )t yields a
t Vmax = 1/Slope (units of mg L1 h1 ).
straight line (Fig. 15.7).
On this plot, the intercept is 1/Vmax . So The intercept is Km /Vmax .

Vmax = 1/Intercept. Intercept (h) Vmax (mg L1 h1 )

= Km (mg L1 ).
The slope of the plot is given by Km /Vmax .
Thus using two corresponding sets of values on
the line for x and y, the slope will equal (Y2 Estimation of MichaelisMenten
Y1 )/(X2 X1 ) and will have units of (h L mg1 )/ parameters following administration of
(L mg1 ) = h (i.e., units of time). multiple doses
The calculated slope then equals Km /Vmax .
If the drug is administered on a multiple-dosing basis,
then the rate of metabolism (or elimination) at steady
Slope (h) Vmax (mg L1 h1 )
state will be a function of the steady-state plasma
= Km (mg L1 ). concentration; i.e., (Cp )ss :

80
70
60
(h mg1 L)

(h)

50
Slope = 1/Vmax
(Cp/t)t

Slope = Km /Vmax 40
(Cp)t
(Cp/t)t

30
1

20
Intercept = 1/Vmax 10
Intercept = Km /Vmax
0
1/Cp (L mg1) 0 5 10 15 20 25 30 35
(Cp)t (mg L1)

Figure 15.7 LineweaverBurke plot to estimate the

fundamental pharmacokinetic parameters of a drug that Figure 15.8 Wolfs plot to estimate the fundamental
exhibits nonlinear kinetics. Km , MichaelisMenten constant; pharmacokinetic parameters of a drug that exhibits nonlinear
Vmax , maximum velocity. kinetics. Abbreviations as in Fig. 15.7.
 Nonlinear pharmacokinetics 329

Elimination rate or metabolism rate

Intercept = Vmax
dX
=
dt
Vmax (Cp )ss
= .

R (mg day 1)
Km + (Cp )ss Slope = Km

Note that at steady state, the rate of elimination is

equal to the drug dosing rate (R):

Vmax (Cp )ss

R= . (15.8)
Km + (Cp )ss
R/(Cp)ss (L day 1)

In order to estimate Vmax and Km , Eq. (15.8) must

first be linearized. The following approach may be Figure 15.9 The use of dosing rate (R) and the
used. Equation (15.8) is rearranged as follows. corresponding steady-state plasma concentrations to obtain
the pharmacokinetic parameters for a drug that exhibits
R[Km + (Cp )ss ] = V max (Cp )ss
nonlinear kinetics. Abbreviations as in Fig. 15.7.
RKm + R(Cp )ss = Vmax (Cp )ss
and evaluate Vmax in a patient. The two rates will be
R(Cp )ss = Vmax (Cp )ss RKm
R1 = Vmax [Km R1 /(Cp1 )ss ] (15.10)
R = [Vmax (Cp )ss RKm ]/(Cp )ss
(15.9) R2 = Vmax [Km R2 /(Cp2 )ss ]. (15.11)
R = Vmax [Km R/(Cp )ss ].
Now, the slope of the line connecting the points
Equation (15.9) indicates that a plot of R versus [R1 , R1 /(Cp1 )ss ] and [R2 , R2 /(Cp2 )ss ] will equal
R/(Cp )ss will be linear, with a slope of Km and a 1Y/1X, or
y-axis intercept of Vmax .
To construct such a plot and estimate the values R1 R2
R1 R2
.
of MichaelisMenten parameters (i.e., Vmax and Km ), (Cp1 )ss (Cp2 )ss
one needs at least two sets of doses (three or four
Substituting the values of R1 and R2 from Eqs (15.10)
is ideal) along with their corresponding steady-state
and (15.11) into the numerator of the above expres-
plasma concentration values.
sion yields

Vmax Km (CRp11)ss Vmax + Km (CRp22)ss

Calculation of Km from two steady-state R1 R2
drug concentrations arising from two (Cp1 )ss (Cp2 )ss

infusion rates Km (CRp11)ss + Km (CRp22)ss

= R1 R2
.
The equation derived above (Eq. 15.9) can be used (Cp1 )ss (Cp2 )ss
to derive two steady-state drug concentrations (e.g.,
Upon simplification, this slope equals
for a drug such as phenytoin, which undergoes
capacity-limited metabolism) arising from two infu- h
R2 R1
i
Km (Cp2 )ss (Cp1 )ss
sion rates: = Km .
R1 R2
(Cp1 )ss (Cp2 )ss
R = Vmax [Km R/(Cp )ss ].
Once we have the value of Km = slope, we
This equation forms the basis for the linear plot of can obtain the patients Vmax by rearrangement of
R versus R/(Cp )ss , as seen in Fig. 15.9, with a slope of Eq. (15.8), as follows:
Km and a y-axis intercept of Vmax . In practice, two
pairs of infusion-ratesteady-state drug concentration R[Km + (Cp )ss ]
Vmax = .
data will suffice to define the straight line of this plot (Cp )ss
330 Basic Pharmacokinetics

Example: estimation of dosing rate (R) and For 300 mg dose:

steady-state plasma concentration (Cp )ss
6.5 mg L1 300 mg day1
for phenytoin from MichaelisMenten (Cp )ss =
548 mg day1 300 mg day1
parameters
(Cp )ss = 7.86 mg L1 .
If the MichaelisMenten parameters are known in a
patient or are reported in the literature, the dosing For 450 mg dose:
rate necessary to obtain a desired steady-state plasma
concentration can be estimated. 6.5 mg L1 4540 mg day1
(Cp )ss =
For example, for phenytoin, the estimated values 548 mg day1 450 mg day1
of Km and Vmax are 6.5 mg L1 and 548 mg day1 , re-
spectively. It is desired to obtain a steady-state plasma (Cp )ss = 29.84 mg L1 .
concentration of 15 mg L1 . The dosing rate can be 1 What (Cp )ss would be achieved by a 548 mg
determined from Eq. (15.8): day1 dose?
Vmax (Cp )ss 2 Construct a plot of (Cp )ss versus administered
R= dose.
Km + (Cp )ss
548 mg day1 15 mg L1
R=
6.5 mg L1 + 15 mg L1 15.4 Relationship between the
= 382 mg day1 . area under the plasma
Alternatively, if the MichaelisMenten parameters concentration versus time
and the administered dosing rate are known, the curve and the administered
steady-state plasma concentration can be predicted. dose
Equation (15.8) may be rearranged to solve for (Cp )ss :
For a single intravenous bolus eliminated by a
Km R first-order process:
(Cp )ss = . (15.12)
Vmax R Z
(Dose)
In the earlier example, if a dose of 400 mg day1 (AUC) 0 = Cp dt = (15.13)
0 VK
is administered,
whereas for nonlinear kinetics, capacity-limited
6.5 mg L1 400 mg day1 kinetics, or MichaelisMenten kinetics:
(Cp )ss =
548 mg day1 400 mg day1 Z
(AUC) 0 = Cp dt
(Cp )ss = 17.56 mg L1 . 0

Using Eq. (15.12) and administered daily doses

 
(Cp )0 (Cp )0
= + Km . (15.14)
of phenytoin of 100, 200, 300, and 450 mg, the Vmax 2
steady-state plasma concentration can be calculated
for each dose.
High doses
For 100 mg dose:
At high single doses or when (Cp )0 Km , the value
6.5 mg L1 100 mg day1
(Cp )ss = of Km in Eq. (15.14) is negligible.
548 mg day1 100 mg day1
(Cp )20
Z
(Cp )ss = 1.45 mg L1 . (AUC) 0 = Cp dt =
0 2(Vmax )
For 200 mg dose:
(X0 )2
1 1 = (15.15)
6.5 mg L 200 mg day 2(Vmax )(V)2
(Cp )ss =
548 mg day1 200 mg day1 where V is the apparent volume of distribution and
(Cp )ss = 3.73 mg L1 . X0 is the dose administered.
 Nonlinear pharmacokinetics 331

Equation (15.15) shows that, for a single, rela- kinetics (Eq. 15.14):
tively high dose of phenytoin, if you double the Z  
dose, the AUC will increase by four times, while (Cp )0 (Cp )0
(AUC)
0 = Cp dt = + Km .
tripling the dose will increase plasma concentration 0 Vmax 2
nine times. In other words, (AUC) 0 is proportional
For 100 mg dose:
to the square of the dose. Therefore, a relatively
modest increase in the dose may produce a dramatic
(Cp )0 = Dose/V = 100 mg/50 L = 2 mg L1
increase in the total AUC. The effect of increasing
2 mg L1
Z
the size of doses of phenytoin that will be given in (AUC) = Cp dt =
0
a multiple-dosing regimen can have even more dra- 0 10.96 mg L1 day1
matic effects. As mentioned in the introduction to " #
2 mg L1
this chapter, increasing the daily dose of phenytoin to + 6.5 mg L1

a size that is large (compared with Vmax ) can cause 2

steady-state phenytoin concentrations to skyrocket. = 1.37 mg L1 day.
In fact, daily doses equal to or greater than a pa-
tients maximum rate of metabolism (Vmax ) will cause For 200 mg dose:
phenytoin concentrations to increase without an up-
per limit! These assertions can be validated by use of (Cp )0 = Dose/V = 200 mg/50 L = 4 mg L1
Eq. (15.12).
4 mg L1
Z
(AUC) 0 = Cp dt =
0 10.96 mg L1 day1
Low doses " #
4 mg L1 1
+ 6.5 mg L
At low doses: When (Cp )0 Km , or (Cp )0 /2 Km , 2
the value of (Cp )0 /2 in Eq. (15.14) is ignored because
it is much smaller than the value of Km . = 3.10 mg L1 day.
Z
(Cp )0 Km For 300 mg dose:
(AUC)
0 = Cp dt = .
0 Vmax
(Cp )0 = Dose/V = 300 mg/50 L = 6 mg L1
Moreover, Vmax /Km = K. Therefore, Km /Vmax =
6 mg L1
Z
1/K and (Cp )0 = Dose/V, which yields Eq. (15.13): (AUC) Cp dt =
0 =
0 10.96 mg L1 day1
Dose
(AUC)
0 = . " #
VK 6 mg L1 1
+ 6.5 mg L
For example, for phenytoin, the reported values 2
of the apparent volume of distribution and Vmax are = 5.20 mg L1 day.
50 L and 548 mg day1 , respectively. Determine the
(AUC) 0 following the daily administration of 100, For 450 mg dose:
200, 300, and 450 mg doses of phenytoin. Remem-
ber that, for phenytoin, the literature average Km = (Cp )0 = Dose/V = 450 mg/50 L = 9 mg L1
6.5 mg L1 .
9 mg L1
Z
(AUC) 0 = Cp dt =
Vmax = 548 mg day1 /50 L 0 10.96 mg L1 day1
" #
= 10.96 mg L1 day1 . 9 mg L1 1
+ 6.5 mg L
2
This situation does not qualify for use of the
high-dose equation (Eq. 15.15). Neither are the = 9.03 mg L1 day.
plasma drug concentrations obtained small enough to
warrant use of the low-dose (linear kinetic) equation Using these data, a plot of (AUC) 0 against the
(Eq. 15.13). This leaves the requirement to use the administered dose can be constructed. From the plot,
general equation for MichaelisMenten elimination make an observation of the relationship.
332 Basic Pharmacokinetics

15.5 Time to reach a given fraction Multiplying through by Vmax R:

of steady state RKm + (Vmax R)(Cp )t
Km ln
RKm + (Vmax R)(Cp )0
In nonlinear elimination pharmacokinetics, the time 
required to reach a given fraction of the steady-state (Cp )t (Cp )0
concentration varies with the rate of drug administra-
tion and depends upon the values of Vmax and Km . For

RKm RKm + (Vmax R)(Cp )t
a constant rate of infusion or input, the rate of change ln
(Vmax R) RKm + (Vmax R)(Cp )0
of a drug in the body, V(dCp /dt), is the difference
(Vmax R)
between the rate drug in and the rate drug out: = t
V
dCp Vmax Cp which equals
V =R
dt Km + Cp
RKm + (Vmax R)(Cp )0
RKm + RCp Vmax Cp + Km ln
= . RKm + (Vmax R)(Cp )t
Km + Cp 
Collecting terms with their appropriate differentials: (Cp )t (Cp )0

Km + Cp 1 +RKm RKm + (Vmax R)(Cp )0
dCp = dt. ln
RKm + (R Vmax )Cp V (Vmax R) RKm + (Vmax R)(Cp )t
(Vmax R)
Multiplying numerator and denominator of the left = t.
V
side by 1 and splitting terms:
Multiplying the first term by unity in the form of
Km (Vmax R)/(Vmax R) and expanding yields
dCp
RKm + (Vmax R)Cp
Cp Km Vmax RKm + (Vmax R)(Cp )0
+ dCp ln
RKm + (Vmax R)Cp Vmax R RKm + (Vmax R)(Cp )t
1 Km R RKm + (Vmax R)(Cp )0
= dt. ln
V Vmax R RKm + (Vmax R)(Cp )t

Integrating from (Cp )0 to (Cp )t :
+ (Cp )t + (Cp )0
Z (Cp )t
1 
Km dCp +RKm RKm + (Vmax R)(Cp )0
(Cp )0 RKm + (Vmax R)Cp + ln
(Vmax R) RKm + (Vmax R)(Cp )t
Z (Cp )t
Cp (Vmax R)
+ dCp = t.
(Cp )0 RKm + (Vmax R)Cp V
Z t
1 Cancellation of terms yields
= dt.
V 0
Km Vmax RKm + (Vmax R)(Cp )0
Performing the integrations (using Selby (1970), ln
Vmax R RKm + (Vmax R)(Cp )t
integrals 27 and 30 for the first two terms):

Km RKm + (Vmax R)(Cp )t + [(Cp )t ] + (Cp )0

ln
Vmax R RKm + (Vmax R)(Cp )0
(Vmax R)

(Cp )t (Cp )0 = t.
V
Vmax R Vmax R
 Multiplying both numerator and denominator of the
RKm RKm + (Vmax R)(Cp )t logarithmic expression by 1 yields
ln
(Vmax R)2 RKm + (Vmax R)(Cp )0
1 Km Vmax +RKm (Vmax R)(Cp )0
= t. ln
V Vmax R +RKm (Vmax R)(Cp )t
 Nonlinear pharmacokinetics 333

 
+ [(Cp )t ] + (Cp )0 Km V 1
Vmax ln fss R = tfss .
(Vmax R)2 1 fss
(Vmax R)
= t. (15.22)
V
Rearranging to solve for t, the time to go from (Cp )0 For the commonly used fss = 0.9, we obtain
to (Cp )t , yields
Km V
(Vmax ln(10) 0.9R)
Km Vmax V RKm (Vmax R)(Cp )0 (Vmax R)2
ln
(Vmax R)2 RKm (Vmax R)(Cp )t Km V
= (2.303Vmax 0.9R) = t0.9 .
V(Cp )t V(Cp )0 (Vmax R)2
+ (15.23)
Vmax R Vmax R

= t. (15.16) Dimensional analysis

If the starting condition is (Cp )0 = 0, then
The dimensions will be
Km Vmax V RKm
ln (mg L1 )(L)
(Vmax R)2 RKm (Vmax R)(Cp )t (2.303 [mg day1 ]
(mg day1 )2
V(Cp )t

Vmax R 0.9 [mg day1 ])
= t. (15.17) mg
= = time (days).
(mg day1 )
If the objective is to determine how much time
it will take to reach a given fraction of the drug It is clear from Eq. (15.23) that the time required
concentration that will be achieved at steady state to reach 90% of steady state for drugs with nonlinear
(i.e., (Cp )t = fss (Cp )ss ), then Eq. (15.12) needs to be kinetics is affected by the dosing rate (R) as well
modified as follows: as the values of Vmax , Km , and the apparent volume
fss Km R of distribution (V) of the drug. For a given drug,
(Cp )t = (15.18) however, the time required to attain a given frac-
Vmax R
tion of the steady-state concentration is determined
and by the chosen rate of drug administration (R), the
other parameters being constant for a particular drug
(Vmax R)(Cp )t = fss Km R. (15.19)
administered to a particular patient.
Now the expression in Eq. (15.18) for (Cp )t and
the expression in Eq. (15.19) for (Vmax R)(Cp )t can
both be substituted into Eq. (15.17): 15.6 Example: calculation of
Km Vmax V RKm parameters for phenytoin
ln
(Vmax R)2 RKm fss RKm

fss RKm V
The time required to attain 90% of the
= tfss . (15.20) true steady-state plasma concentration
(Vmax R)2
for phenytoin
Cancellation yields
Km Vmax V 1 fss RKm V Let us assume that we are interested in deter-
ln = tfss . mining the time required to attain 90% of the
(Vmax R)2 1 fss (Vmax R)2
true steady-state plasma concentration for phenytoin,
(15.21)
which is administered at different rates, where V =
Combining common factors gives the expression 50 L, Vmax = 500 mg day1 and Km = 4 g mL1
for time to go from an initial concentration of zero to (= 4 mg L1 ). Using Eq. (15.23), the time required to
the concentration achieved at a particular fraction of attain 90% of the steady-state concentration can be
steady state: determined for various daily doses.
334 Basic Pharmacokinetics

For 100 mg dose: Table 15.1 Time (t0.9 ) to 90% of steady-state

plasma concentration (Cp )ss level as a function of
(4 mg L1 )(50 L)
(2.303[500 mg day1 ] daily dose (R); Km = 4.0 mg L1
(400 mg day1 )2
R (mg day1 ) t0.9 (days) 0.9(Cp )ss (mg L1 )
0.9[100 mg day1 ]) = 1.33 days.
100 1.33 0.90

For 200 mg dose: 200 2.16 2.40

300 4.41 5.10
(4 mg L1 )(50 L) 1
(2.303[500 mg day ] 400 15.8 14.4
(300 mg day1 )2
0.9[200 mg day1 ]) = 2.16 days. Table 15.2 Time (t0.9 ) to 90% of steady-state
plasma concentration (Cp )ss level as a function of
For 300 mg dose:
daily dose (R); Km = 5.7 mg L1
(4 mg L1 )(50 L) R (mg day1 ) t0.9 (days) 0.9(Cp )ss (mg L1 )
(2.303[500 mg day1 ]
(200 mg day1 )2 100 1.90 1.28
1 200 3.08 3.42
0.9[300 mg day ]) = 4.41 days.
300 6.28 7.27
For 400 mg dose: 400 22.5 20.5

(4 mg L1 )(50 L) following expression:

(2.303[500 mg day1 ]
(100 mg day1 )2
RKm
0.9[400 mg day1 ]) = 15.8 days. Vmax = + R. (15.25)
(Cp )ss
What plasma phenytoin concentrations would be Thus,
achieved at the times and doses above? The answer
RKm
is that slight modifications of the steady-state pheny- Vmax R = . (15.26)
(Cp )ss
toin concentration can be made as follows (using
Eq. 15.12): Substitution of the above expressions for Vmax and
(Vmax R) into Eq. (15.22) results in
0.9(Cp )ss = 0.9Km R/(Vmax R). (15.24)   
V(Cp )ss (Cp )ss 1
From this a table can be constructed (Table 15.1). tf ss = ln fss
R Km 1 fss
What if Km was equal to 5.7 mg L1 instead of 
1
4 mg L1 ? The answer is that, since Km appears only + ln . (15.27)
1 fss
in the numerator of Eq. (15.23), there is a direct
proportion between Km and the time to reach 90% For fss = 0.9, this equals
of the steady-state phenytoin concentration. Similarly,  
the value 0.9(Cp )ss is also directly proportional to Km . V(Cp )ss (Cp )ss
t0.9 = 1.403 + 2.303 . (15.28)
Therefore, each of the above values can be multiplied R Km
by the factor (5.7/4.0), resulting in the figures given in
Table 15.2. The time required for plasma phenytoin
concentration to decline from an initial
Alternative equation to calculate the time to value (Cp )0 to a particular value (Cp )t
reach a given fraction of steady state
Rate of metabolism, or more generally elimination, is
If Vmax is not known but the desired steady-state
the decrease of plasma drug concentration over time.
drug (e.g., phenytoin) concentration is known, a dif-
Therefore, Eq. (15.1) can be rewritten as
ferent equation must be used to calculate the time
required to reach a given fraction of steady state. dCp Vmax Cp
Equation (15.8) can be easily rearranged to the = .
dt Km + Cp
 Nonlinear pharmacokinetics 335

Collecting terms with their appropriate differentials: Solution

dCp The average percentage phenytoin bound to plasma
(Km + Cp ) = Vmax dt. proteins is 89%, which corresponds to a percentage
Cp
free equal to 100 89 = 11%. Expressed as a
Expanding: decimal, the nominal free fraction of phenytoin
Km is 0.11. This is termed the fraction unbound in the
dCp dCp = Vmax dt. plasma (fup ).
Cp
A reasonable total phenytoin concentration at
Taking integrals for t = 0 to t = t: steady state is in the middle of the therapeutic range:
Z (Cp )0 Z (Cp )0
1 15 g mL1 . Since unbound drug concentration is
dCp Km dCp equal to the free fraction times the total drug con-
(Cp )t (Cp )t C p
Z t centration, we define:
= Vmax dt. (Cp )free = fup Cp . (15.31)
0

Performing the integration: Therefore, a patient with a nominal free fraction

(Cp )0 of phenytoin will have a target free phenytoin concen-
(Cp )0 (Cp )t + Km ln = Vmax t. (15.29) tration of (0.11) (15 g mL1 ) = 1.65 g mL1 .
(Cp )t
Target total plasma concentrations will be dif-
In this case Vmax would have units of concentra- ferent for different free fractions; however, the tar-
tion per unit time. For Vmax expressed in units of mass get free plasma phenytoin concentration remains
per unit time, the equation would be 1.65 g mL1 . That is, this value is invariant, regard-
(Cp )0 Vmax less of the patients free phenytoin fraction.
(Cp )0 (Cp )t + Km ln = t. (15.30) This fact can be used when Eq. (15.31) is re-
(Cp )t V
arranged to solve for the target total phenytoin
Free and total plasma phenytoin concentration in the patient in this example:
concentrations
Target (Cp )free
Target (Cp )patient =
Only unbound (free) drug is capable of exerting phar- (fup )patient
macological (or toxic) effect. The following example
depicts the adjustments required in the case of an 1.65 g mL1
=
atypical free fraction of phenytoin in the blood. 0.22

Problem
A patient with hypoalbuminemia has a phenytoin free
fraction of 0.22. Calculate a reasonable target total
(free + bound) plasma phenytoin concentration in
this patient.
= 7.50 g mL1 .
Notice that, in this problem, the patients free frac-
tion is twice normal; so, her total plasma phenytoin
concentration requirement is exactly one-half of the
usual 15 g mL1 .
Problem set 8
Problems for Chapter 15
Calculations
Question 1
Patient A.B., a 40-year-old woman weighing
67 kg, presented to the hospital emergency room
with epileptiform seizures. A phenytoin assay
shows no phenytoin in the plasma. In the ab-
sence of individual pharmacokinetic parameters,
the literature average values should be used:
maximum reaction rate (Vmax ) = 7.5 mg
kg1 day1 .
MichaelisMenten constant (Km ) = 5.7
mg L1
volume of distribution (V) = 0.64 L kg1
salt value for sodium phenytoin = 0.916
absolute oral bioavailability (FPO ) = 0.98.
(a) Suggest a loading dose of intravenous
sodium phenytoin, (DL )IV , for this patient.
Base the desired plasma concentration,
(Cp )desired , on a maximum concentration
(Cp )max of 20 mg L1 .
(b) The patient has been stabilized by a series
of short intravenous infusions of sodium
phenytoin. For a target average phenytoin
concentration of 15 mg L1 , calculate a
daily oral maintenance dose (Do ) of sodium
phenytoin for this patient.
(c) If sodium phenytoin capsules are available
in 100 mg and 30 mg strengths, what com-
bination of these will closely approximate
the daily dose of sodium phenytoin calcu-
lated in part (b)?
(d) One month later, the patients regimen is
to be reviewed. Steady-state plasma con-
centrations from two different dosage rates
have shown that this patients Vmax equals
10 mg kg1 day1 and her Km equals
6.0 mg L1 . Calculate a new daily oral
maintenance dose of sodium phenytoin.
(e) What intravenous dosing rate in milligrams
per day of sodium phenytoin would equal
the oral dosing regimen in part (d)?
Question 2
Patient B.C., the identical twin of patient A.B.
in question 1, also weighing 67 kg but with
a history of hypoalbuminemia, presents to the
hospital with epileptiform seizures. A phenytoin
assay shows no phenytoin in the plasma. Pa-
tient B.C. is stabilized by a series of short intra-
venous infusions of sodium phenytoin. Although
her seizures have been stabilized, the patient ex-
hibits a plasma total phenytoin concentration of
only 7.5 mg L1 , prompting the determination
of a free (unbound) phenytoin concentration.
The free phenytoin concentration is 1.65 mg L1 .
In the absence of individual pharmacokinetic
parameters, employ literature average values:
maximum reaction rate (Vmax ) = 7.5 mg
kg1 day1 .
338 Basic Pharmacokinetics

4 MichaelisMenten elimination kinetics is due to

MichaelisMenten constant (Km ) = 5.7 saturation of metabolic sites; while zero-order
mg L1 elimination kinetics is due to partial saturation
volume of distribution (V) = 0.64 L kg1 of these sites.
salt value for sodium phenytoin = 0.916
(A) True
absolute bioavailability (FPO ) = 0.98. (B) False
(a) What is the free fraction of phenytoin in 5 For a drug eliminated by nonlinear kinetics,
patient B.C.? slight errors in the calculation of the optimal
(b) Does the total (bound and free) concentra- daily dose can cause disproportionate changes in
tion of 7.5 mg L1 represent a subtherapeu- the drugs average steady-state plasma drug con-
tic concentration in this patient? centration and corresponding changes in thera-
(c) To what total phenytoin concentration, peutic or toxic effect.
(Cp )total , would this value of 7.5 mg L1 in (A) True
patient B.C. correspond in a patient with
(B) False
normal serum albumin and a normal free
fraction of phenytoin?
(d) Calculate a daily oral maintenance dose of Answers
sodium phenytoin for patient B.C. using the
literature average values. Answers to calculations

Multiple choice and true/false questions Question 1 answer

Answer the following statements by selecting A for (a)

true and B for false or appropriate answer for multiple (DL )IV
choice and numerical value questions. (0.64 L kg1 )(67 kg)(20 mg L1 0 mg L1 )
=
(0.916)(1)
1 A daily oral dose of a drug eliminated by = 936 mg.
MichaelisMenten kinetics will reach practi-
cal steady-state equilibrium in about 4.32 drug
elimination half lives. (b) Daily oral maintenance dosage:

(A) True Do Vmax (Cp )

=
(B) False [Km + (Cp ) ](SFPO )
(7.5 mg kg1 )(67 kg)(15 mg L1 )
2 Doubling the daily dose of a drug eliminated by =
(5.7 mg L1 + 15 mg L1 )(0.916)(0.98)
MichaelisMenten kinetics will likely more than
double the drugs average steady-state plasma = 406 mg.
drug concentration.
Do = 406 mg sodium phenytoin daily.
(A) True (c) Four capsules of 100 mg.
(B) False (d) Revised daily oral maintenance dose:
 
3 Doubling the intravenous bolus dose of a drug Do
eliminated by MichaelisMenten kinetics would PO
more than double the area under the plasma (10 mg kg1 )(67 kg)(15 mg L1 )
=
drug level versus time curve but would not affect (6 mg L1 + 15 mg L1 )(0.916)(0.98)
the initial plasma drug concentration, (Cp )0 . = 533 mg.
(A) True
Do = 533 mg sodium phenytoin daily.
(B) False
 Problem set 8 339

(e) Daily intravenous dose equivalent to oral This reflects the fact that more phenytoin is
dose of 533 mg: available for elimination when the free fraction
 
Do is higher than normal. In patient B.C., a dose
= (533 mg)(0.98) = 522 mg. based on a target total phenytoin concentration
IV
of 15 mg L should achieve a steady-state concen-
DIV = 522 mg sodium phenytoin daily. tration:
 
0.11
(Cp )total = (15 mg L1 )
0.22
= 7.5 mg L1
Question 2 answer
and a therapeutic free phenytoin concentration,
(a) The free fraction is given by
(Cp )free = 0.22 7.5 mg L
(Cp )free 1.65 mg L1
= = 0.22.
(Cp )total 7.5 mg L1 = 1.65 mg L1 .

(b) In fact a free phenytoin concentration of
1.65 mg L1 is in the midrange of the thera-
peutic window for phenytoin and, as such,
represents a useful target.
(c) Since the normal free fraction of phenytoin
is 0.11, the total phenytoin concentration in
a normal person would be
(Cp )total 0.11 = 0.22 7.5 mg L1
= 15 mg L1 .
(d) To calculate a daily dose using the
MichaelisMenten equation, the target
(Cp )total of 7.5 mg L1 is not used. Instead,
the value used is the (Cp )total to which
the observed concentration of 7.5 mg L1
would correspond if this patient had a
normal free fraction. The adjusted total
phenytoin concentration, calculated above
in (c), equals 15 mg L1 . This adjusted value
is used in the MichaelisMenten equation.
Now, we can calculate the daily oral dose:
Xo Vmax (Cp )adjusted
=
[Km + (Cp ) ](SFPO )
(7.5 mg kg1 )(67 kg)(15 mg L1 )
=
(5.7 mg L1 + 15 mg L1 )(0.916)(0.98)
= 406 mg.
Notice that this is the same daily dose as used
in patient A.B. above, the identical twin with
normal serum albumin and a normal phenytoin
free fraction of 0.11.
We expect that 400 mg day1 of oral sodium
phenytoin will produce a (Cp )total of 7.5 mg
L1 and a (Cp )free of 1.65 mg L1 in patient B.C.
Answers to multiple choice and true/false
questions
1 B; 2 A; 3 A; 4 B; 5 A.