Drug Metabolism in Drug Design and Development Basic Concepts and Practice

inhibitor (usually [I]max,ss). If the drug elimination is due largely to a CYP
(fm= 1), Equation 16.8 can be simplified to Equation 16.9.

AUC½IŠ

AUCctr

¼ 1 þ

fu;p½IŠ

Ki

ð 16 : 9 Þ

The clinical implications of CYP inhibition by inhibitors are dependent on
thein vivoconcentration of the inhibitor and the role of that CYP in the
metabolism of the coadministered drug (fm) (Table 16.6). Clinical relevance of
competitive CYP inhibition to human DDI prediction is given in Table 16.7
(Bjornsson et al., 2003a, 2003b). The equations are used to quantitatively
predict DDI potential in human fromin vitrocompetitive, noncompetitive and
mixed type inhibition. As a conservative approach, the inhibitor [I]maxat
steady-state and at the highest clinical dose expected should be used in the
estimation of AUC change. It was found that a DDI would likely occur if the
ratio of inhibitor [I]max/Kiwere greater than 1 (Table 16.7). DDIs at the ratios
between 1 and 0.1 or below 0.1 are possible or remote.

16.5.2 Prediction of Human Drug–Drug Interactions from Mechanism-Based
CYP Inhibition

The ability to accurately predict DDI secondary to MBI of a CYP(s) has been
greatly enhanced by the knowledge of the specific CYP-mediated reactions,

TABLE 16.7 Prediction of clinical relevance of

competitive CYP inhibition (Bjornsson et al., 2003a, 2003b).

[I]/Ki Prediction

[I]max/Ki> 1 Likely

1 >[I]max/Ki>0.1 Possible

0.1>[I]max/Ki Remote

TABLE 16.6 Fractions of metabolism of substrates by individual CYPs reported in
literature.

Substrate fm Substrate fm

Alprazolam 0.8 Midazolam 0.99 (0.94)
Buspirone 0.99 Nifedipine 0.71
Carbamazepine 0.6 Nisoldipine 0.99
Cisapride 0.95 Pimozide 0.4
Cyclosporine 0.71 Quinidine 0.76
Diazepam 0.8 Simvastatin 0.99
Felodipine 0.99 (0.81) Taxol 0.7–0.9
Loratadine 0.6 Terfenadine 0.74
Lovastatin 0.99 Triazolam 0.98

PREDICTION OF HUMAN DRUG–DRUG INTERACTIONS 535