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.