Prediction of DDI
The PBPK modeling of above drugs and the DDI module of GastroPlus were
utilized to predict the potential pharmacokinetic (PK) changes that may
occur when combining a substrate and ketoconazole. After confirming the
PBPK models of the substrate and inhibitor, we used the DDI module of
GastroPlus to predict the potential PK changes resulting from the
combination of the two compounds. The DDI module accounted for the
clearance of the substrate, which includes three components: the
metabolism of CYP3A4 (with its fm value
determined via in vitro experiments), the metabolism of
non-CYP3A4 enzymes, and renal excretion. We used the default inhibition
constant of CYP3A4 (Ki = 0.015 μM) in the PBPK model of ketoconazole.
The administration regimen for the combination of the substrate and
inhibitor were summarized in Table S3. Using the dynamics of substrates
and Ketoconazole, we simulated the DDI potential based on the dynamics,
Ki value, and fm . The DDI potential was
calculated using the following equations:
TmaxR = Tmax, i/Tmax
CmaxR = Cmax, i/Tmax
AUCR = AUCi / AUC
where Tmax, i, Cmax, i, and
AUCi are the parameters of drugs when co-administered
with ketoconazole, and Tmax, Cmax, and
AUC are the parameters of the drug when administered alone.