Physiologically-based modeling of cholate disposition in beagle dog with and without treatment of the liver transporter inhibitor simeprevir

Abstract

BSEP inhibition is one risk factor for Drug-Induced Liver Injury (DILI). While in vitro screening of BSEP inhibition may prevent compounds with BSEP liability from progressing into the clinic, these in vitro data alone can result in false-positives and as such a specific in vivo biomarker would further enhance our BSEP inhibition de-risking strategy. Measurement of endogenous bile acids as biomarkers of BSEP inhibition in vivo is complicated by several factors, including drugs that inhibit BSEP can also inhibit other bile acid transporters such as NTCP. Here, we developed a novel translational framework, including an in vivo biomarker with a corresponding mechanistic model, and attempted to decouple the effect of liver sinusoidal uptake inhibition from efflux inhibition on bile acid disposition in the beagle dog. Specifically, we hypothesized that the change of a stable isotope-labeled (SIL) bile acid tracer’s exposure would yield a toxicodynamic signal that can provide insight into BSEP inhibition and ensuing bile salt accumulation. For this purpose we dosed the stable isotope-labeled cholic acid (13C-CA) and taurocholic acid (D4-TCA) as biomarker tracers in dogs, with and without the liver transporter inhibitor simeprevir, and determined the plasma and bile exposure of 13C-CA, 13C-TCA, D4-CA and D4-TCA in vivo. Key bile acid clearance and transporter inhibition parameters were determined in vitro. We developed a novel Physiologically Based Pharmacokinetic model (PBPK) to integrate the mechanistic physiological understanding, literature knowledge, and in vitro laboratory data to model bile acid disposition. Using modeling and simulation, we provided an increased mechanistic understanding of how to use plasma bile acid tracer data to inform on potential liver transporters inhibition and limitations to in vivo translation. The novel translational framework can enhance the future BSEP inhibition de-risking strategy, particularly if the experimental confounders to studying kinetics in dog hepatocytes in vitro models are solved.