Drug Metabolism in Drug Design and Development Basic Concepts and Practice

clinical dose as inhibitor concentrations [I] for prediction. This is a
conservative way to calculate the ratio. Table 7.5 lists examples of predicted
and observed magnitude of drug interactions between ketoconazole and
triazolam. Using both total and unbound fractions to predict the fold increase
in AUC indicates that there is huge discrepancy between predicted and
observed studies using total and unbound fractions. Although most drugs are
better predicted using the unbound fraction rather than total concentrations, it
is a conservative measure to use the total concentrations for regulatory use
because there are a few exceptions, i.g. itraconazole, where the prediction using
unbound fractions is much underestimated.
Alternatively, an IC 50 can be used for prediction since IC 50 andKiare
correlated (Fig. 7.2). In general, the IC 50 value is greater than or equal to the

TABLE 7.5 Effect of ketoconazole on oral triazolam AUC using mean reportedKi
value, total concentrations (bound + unbound fractions) ofCmaxand unbound
fraction ofCmax(Iu) as [I] for prediction compared with actually observedin vivo
study results.

Dose

Cmax

(mM) fu Iu

Kia

(mM)

AUCi/AUCc

1+Cmax/Ki 1+Iu/Ki Observed

200 mg S.D. 9.3 0.01 0.093 0.0165 565 6.6 9 b
200 mg, Q12 2.5 days 10 0.01 0.10 0.0165 607 7.1 13.7c
400 mg, QD 4 days 15 0.01 0.15 0.0165 910 9.1 22.4d

aMean value from published reports.
bvon Moltke et al. (1996).
cGreenblatt et al. (1998).
dVarhe et al. (1994).

FIGURE 7.2 Comparison of observed and predicted AUC changes of saquinavir with
coadministration of ritonavir using different IC 50 values from different substrates (data
from University of Washington Drug Metabolism database).

222 REGULATORY CONSIDERATIONS OF DRUG METABOLISM AND DRUG