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 (PS inf ) obtained in the absence of albumin, but failed in capturing the blood PMF pharmacokinetic (PK) profiles. Based on the results that in vitro PS inf of unbound PMF was enhanced in the presence of albumin, we applied the albumin-facilitated dissociation model and the resulting PS inf 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 (K i,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.

Febuxostat and its major acyl glucuronide metabolite are potent inhibitors of organic anion transporter 3: Implications for drug‐drug interactions with rivaroxaban

“…The use of 5% HSA in the uptake buffer mimics physiological albumin concentration, thereby allowing an accurate in vivo assessment of febuxostat—which is known to be highly protein bound (∼99.2%) to albumin (Takeda Pharmaceuticals, 2009). At this juncture, although we are cognisant that pooled human plasma would yield the most accurate prediction as it encompasses interindividual variability and contains albumin binding modulators such as fatty acids (Liebchen et al., 2014; Zeitlinger et al., 2011), the use of 5% HSA as a surrogate has been validated by previous studies to yield sufficiently accurate inhibitory kinetic parameters (Miyauchi et al., 2018; Park et al., 2021). Consistent with these previous reports, we observed a ∼7.5‐fold decrease in the IC 50 of febuxostat when rivaroxaban was adopted as the probe substrate in place of E3S in protein‐free conditions and a further 42.5‐fold decrease in its inhibition potencies after adjusting for f u in experiments performed in the presence of 5% HSA.…”

Preincubation Time-Dependent, Long-Lasting Inhibition of Drug Transporters and Impact on the Prediction of Drug−Drug Interactions

“…Figure 1 Preincubation preincubation (for 30 minutes or longer) using atorvastatin, BSP, E 2 G, E 1 S, pemafibrate, pitavastatin, rosuvastatin, fluvastatin, or pravastatin as a probe substrate (Amundsen et al, 2010;Gertz et al, 2013;Izumi et al, 2015;Taguchi et al, 2019;Tátrai et al, 2019;Taguchi et al, 2020;Park et al, 2021). The in vivo K i values of CsA, which were able to reproduce clinical DDIs with statis, were previously estimated using PBPK modeling (Varma et al, 2012;Yoshikado et al, 2016).…”