Improved Prediction of the Drug-Drug Interactions of Pemafibrate Caused by Cyclosporine A and Rifampicin via PBPK Modeling: Consideration of the Albumin-Mediated Hepatic Uptake of Pemafibrate and Inhibition Constants With Preincubation Against OATP1B

Pemafibrate (PMF) is highly albumin-bound (>99.8%) and a substrate for hepatic uptake transporters (OATP1B) CYP enzymes. Here, we developed PBPK model of PMF to capture drug-drug interactions (DDI) incurred by cyclosporine (CsA) rifampicin (RIF), the two OATP1B inhibitors. Initial modeling utilized in vitro clearance (PSinf) obtained absence albumin, but failed capturing blood pharmacokinetic (PK) profiles. Based on results that PSinf unbound was enhanced presence applied albumin-facilitated dissociation resulting parameters improved prediction PK In refining our toward observed DDI data (PMF co-administered with single dosing CsA or RIF; following multiple RIF dosing), adjusted previously vivo inhibition constants (Ki,OATP1B) pitavastatin correcting substrate-dependency. We also incorporated induction enzymes after dosing. Sensitivity analysis informed higher gastrointestinal absorption rate constant could further improve data, suggesting possible intestinal ABC transporter(s) RIF.