Abstract
We verified a physiologically-based pharmacokinetic (PBPK) model to predict cytochrome P450 3A4/5-mediated drug-drug interactions (DDIs). A midazolam (MDZ)-ketoconazole (KTZ) interaction study in 24 subjects selected by CYP3A5 genotype, and liquid chromatography and mass spectroscopy quantification of CYP3A4/5 abundance from independently acquired and genotyped human liver (n = 136) and small intestinal (N = 12) samples, were conducted. The observed CYP3A5 genetic effect on MDZ systemic and oral clearance was successfully replicated by a mechanistic framework incorporating the proteomics-informed CYP3A abundance and optimized small intestinal CYP3A4 abundance based on MDZ intestinal availability (F(G) ) of 0.44. Furthermore, combined with a modified KTZ PBPK model, this framework recapitulated the observed geometric mean ratio of MDZ area under the curve (AUCR) following 200 or 400 mg KTZ, which was, respectively, 2.7-3.4 and 3.9-4.7-fold in intravenous administration and 11.4-13.4 and 17.0-19.7-fold in oral administration, with AUCR numerically lower (P > 0.05) in CYP3A5 expressers than nonexpressers. In conclusion, the developed mechanistic framework supports dynamic prediction of CYP3A-mediated DDIs in study planning by bridging DDIs between CYP3A5 expressers and nonexpressers.