Quantitative Analyses of the Influence of Parameters Governing Rate-Determining Process of Hepatic Elimination of Drugs on the Magnitudes of Drug-Drug Interactions via Hepatic OATPs and CYP3A Using Physiologically Based Pharmacokinetic Models.

Physiologically based pharmacokinetic models were constructed for hepatic organic anion-transporting polypeptides (OATPs) and cytochrome P450 3A (CYP3A) substrates (bosentan, repaglinide, clarithromycin, and simeprevir), a CYP3A probe substrate (midazolam), and selective inhibitors for OATPs (rifampicin) and CYP3A (itraconazole), although the role of OATPs in the hepatic uptake of clarithromycin is unclear. The pharmacokinetic data were obtained from our previous clinical drug-drug interaction (DDI) study. Parameters optimized from clinical PK data were confirmed to reproduce their blood concentrations in control phase. DDIs with rifampicin and itraconazole were simulated using in vivo Rdif (ratio of diffusional uptake to active uptake) and β (the fraction of the sum of intrinsic clearances for metabolism and biliary excretion in all possible itineraries of intracellular drugs including basolateral efflux) estimated by static analyses based on the extended clearance concept, in vivo inhibition constant (Ki) for hepatic OATPs reported previously, and in vivo Ki for CYP3A determined from DDI data with midazolam and itraconazole. Sensitivity analyses showed the magnitudes of DDIs largely depended on Rdif and β. In conclusion, our approach using physiologically based pharmacokinetic modeling showed that the rational estimation of parameters governing rate-determining process of hepatic elimination is critical to accurately predict DDI magnitudes involving OATPs/CYP3A inhibition.