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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 The term linear simply means that plasma concen-
tration at a given time at steady state and the area
Pharmacokinetic parameters, such as elimination half under the plasma concentration versus time curve
life (t1/2 ), the elimination rate constant (K), the appar- (AUC) will both be directly proportional to the dose
ent volume of distribution (V), and the systemic clear- administered, as illustrated in Fig. 15.1.
ance (Cl) of most drugs are not expected to change For some drugs, however, the above situation may
when different doses are administered and/or when not apply. For example, when the daily dose of pheny-
the drug is administered via different routes as a single toin is increased by 50% in a patient from 300 mg to
dose or multiple doses. The kinetics of these drugs is 450 mg, the average steady-state plasma concentra-
described as linear, or dose-independent, pharmacoki- tion, (Cp )ss , may increase by as much as 10-fold. This
netics and is characterized by the first-order process. dramatic increase in the concentration (greater than
324 Basic Pharmacokinetics
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.
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
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)
MichaelisMenten region
0.5
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)
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 .
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)
R (mg day 1)
Km + (Cp )ss Slope = Km
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
+ [(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
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
= 7.50 g mL1 .
Problem
A patient with hypoalbuminemia has a phenytoin free Notice that, in this problem, the patients free frac-
fraction of 0.22. Calculate a reasonable target total tion is twice normal; so, her total plasma phenytoin
(free + bound) plasma phenytoin concentration in concentration requirement is exactly one-half of the
this patient. usual 15 g mL1 .
Problem set 8
(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 Now, we can calculate the daily oral dose:
1.65 mg L1 is in the midrange of the thera-
peutic window for phenytoin and, as such, Xo Vmax (Cp )adjusted
=
represents a useful target. [Km + (Cp ) ](SFPO )
(c) Since the normal free fraction of phenytoin (7.5 mg kg1 )(67 kg)(15 mg L1 )
=
is 0.11, the total phenytoin concentration in (5.7 mg L1 + 15 mg L1 )(0.916)(0.98)
a normal person would be = 406 mg.
(Cp )total 0.11 = 0.22 7.5 mg L1 Notice that this is the same daily dose as used
in patient A.B. above, the identical twin with
= 15 mg L1 .
normal serum albumin and a normal phenytoin
(d) To calculate a daily dose using the free fraction of 0.11.
MichaelisMenten equation, the target We expect that 400 mg day1 of oral sodium
(Cp )total of 7.5 mg L1 is not used. Instead, phenytoin will produce a (Cp )total of 7.5 mg
the value used is the (Cp )total to which L1 and a (Cp )free of 1.65 mg L1 in patient B.C.
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 Answers to multiple choice and true/false
in (c), equals 15 mg L1 . This adjusted value
questions
is used in the MichaelisMenten equation.
1 B; 2 A; 3 A; 4 B; 5 A.