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

Abstract

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