Fig. 17. An FDA general scheme of model-based prediction. In this scheme (
FDA, 2012), the investigational drug (and any metabolite present at ≥25% of the parent drug AUC) is considered as an interacting drug with P450 enzymes. TDI: time-dependent inhibition; DDI: drug-drug interaction; AUC
R (AUC
ratio): AUC
with drug/AUC
without drug; R=1+([I]/
Ki). For R
alt (for oral dosage of P450 3A4 inhibitors), I=I
gut=molar dose/250 mL. For the calculation of AUC
R, A, B, and C denote terms for time-dependent inhibition, induction, and reversible inhibition, respectively, in the gut (subscript g) or liver (subscript h). F
g is the fraction of the drug escaping first-pass intestinal metabolism, and f
m is the fractional contribution of a particular P450 (e.g., 3A4) to the metabolism of the drug in the liver (
Fahmi et al., 2009). A is a function of the rate of degradation of the P450 (
kdeg) and the rate constant for the time-dependent inhibition (
kinactivation), B is a function of parameters associated with induction of the particular P450, and C is a simple ratio of the free inhibitor concentration and
Ki (
Fig. 15) (
Fahmi et al., 2009).
