Drug Metabolism in Drug Design and Development Basic Concepts and Practice

although the prediction of MBI-mediated DDIs is more complicated than that
from reversible CYP inhibition (Brown et al., 2005; Galetin et al., 2005, 2006; Ito
et al., 1998; Kenworthy et al., 1999; Mayhew et al., 2000; Venkatakrishnan et al.,
2001; von Moltke et al., 1998; Yao and Levy, 2002). Equation 16.10 is a
commonly used model for the quantitative prediction of human DDIs (AUC
ratio change in the presence and absence of an inhibitor) fromin vitroMBI
(Brown et al., 2005; Galetin et al., 2006; Mayhew et al., 2000; Wang et al., 2004).

AUC½IŠ

AUC½contrŠ

¼

1

fm

1 þ

kinactfu½IŠ

ðKIþfu½IŠÞkE



0

B

B

@

1

C

C

Aþð^1 fmÞ

ð 16 : 10 Þ

wherefmrepresents the fraction of P450-dependent metabolism catalyzed by the
inhibited CYP;kEthe rate constant for enzyme degradation; [I] the projected
plasma concentration of inhibitor (usuallyCmax,ss);futhe unbound fraction of
inhibitor in plasma. The equation can be modified based on several situations
below. If the drug elimination is due largely to the CYP (fm= 1), Equation 16.10
can be simplified with Equation 16.11. Table 16.8 shows examples of prediction
forin vivoDDI potential fromin vitroMBI data and their comparisons with

TABLE 16.8 Prediction of human DDIs fromin vitromechanism-based CYP3A4
inhibition.

Inhibitor Substrate

[I]p,ssa

(mM) fu,pb fm

KI

(mM)c

kinact

(min^1 )

AUC

(pred)d

AUC
(obs)e
Triazolam 4.28 0.3 0.98 5.5 0.07 7.6 5.3
Clarithromycin Cisapride 0.9 0.3 0.95 5.5 0.07 5.8 3.2
Midazolam 4.28 0.3 0.94 5.5 0.07 10.7 8.4
Simvastatin 4.1 0.16 0.99 10.9 0.05 5.9 6.2
Erythromycin Buspirone 4.1 0.16 0.99 10.9 0.05 5.9 5.9
Midazolam 4.1 0.16 0.94 10.9 0.05 5.6 4.4
Mibefradil Midazolam 10.2 0.005 0.94 2.3 0.4 9.0 8.9
Nelfinavir Simvastatin 7.0 0.015 0.99 1 0.22 8.3 6.1
Ritonavir Triazolam 3.15 0.015 0.98 0.17 0.4 39.1 20.3
Saquinavir Midazolam 1.12 0.02 0.94 0.65 0.26 9.0 5.2
Simvastatin 0.91 0.1 0.99 4.2 0.09 4.7 4.2
Verapamil Buspirone 0.48 0.1 0.99 4.2 0.09 3.0 3.5
Midazolam 0.48 0.1 0.94 4.2 0.09 2.7 2.9

aMaximum plasma concentrations of the inhibitors at steady state reported in literature.
bUnbound fractions of the inhibitors in human plasma.
cKIvalues used were not corrected with unbound fraction of the inhibitors in liver microsomes.
dPredicted AUC ratios fromin vitrodata using Equation 16.10. A half life of (23 hours) for
CYP3A4 degradation was used in the prediction.
eClinical observed AUC ratios reported in literature.

536 ANALYSIS OFIN VITROCYTOCHROME P450 INHIBITION