**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]/

K_{i}). 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 (

k_{deg}) and the rate constant for the time-dependent inhibition (

k_{inactivation}), 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

K_{i} (

Fig. 15) (

Fahmi et al., 2009).