Drug Metabolism in Drug Design and Development Basic Concepts and Practice

approved dose and the shortest dosing interval in humanin vivo studies
(Table 7.7).
This classification is quite useful since information on the clinical evaluation
of substrates and inhibitors is readily available from public domains. The
application of the inhibitor classification system allows generalizations such
that a strong inhibitor of CYP3A does not need to be tested with multiple
CYP3A substrates in order to lead to a warning in the label. A newly identified
strong inhibitor of CYP3A4 can have a class labeling such that it may be
contraindicated for CYP3A4 substrate drugs after a small number of studies.
However, caution must be exercised, because the actual magnitude of
interactions by different strong inhibitors can vary greatly. From the case
study below, we know that the same oral dose and duration of conivaptan
increased simvastatin AUC by 20-fold, but midazolam AUC only by sixfold.
On the contrary, although both ketoconazole and ritonavir are strong
inhibitors of CYP3A4, ritonavir actually produces more severe inhibitory drug
interactions. In a series of CYP3A4 drug interaction studies described in the
vardenafil (LevitraTM) package insert (http://www.fda.gov/cder/foi/label/
2005/021400s004lbl.pdf), ritonavir increased vardenafil AUC by 49-fold
compared to10-fold by ketoconazole (Fig. 7.4). Another case is the interaction

TABLE 7.7 Classification of CYP inhibitors.

Classification

Sensitive substrate

AUC increase CL decrease

Strong inhibitor >5fold 80%#
Moderate inhibitor >2but<5fold 50–80%#
Weak inhibitor >1.25 - but<2fold 20–50%#

0

5

10

15

20

25

30

35

40

45

50

Ritonavir 600

mg bid

Indinavir 800

mg tid

Ketoconazole

200 mg qd

Erythromycin

500 mg tid

Cimetidine 400

mg tid

FIGURE 7.4 AUC fold increase of 5 mg vardenafil after coadministration of various
CYP3A4 inhibitors.

DRUG–DRUG INTERACTION STUDIES 227