Elucidating Contributions of Drug Transporters/Enzyme to Nonlinear Pharmacokinetics of Grazoprevir by PBPK Modeling With a Cluster Gauss–Newton Method

Abstract

Grazoprevir (GZR), a direct-acting agent for hepatitis C virus, is recognized as a substrate for organic anion transporting polypeptide 1B (OATP1B), cytochrome P450 3A (CYP3A), and P-glycoprotein (P-gp). The objective of the present study was to elucidate the contribution of these molecules to the nonlinear pharmacokinetics of GZR using a physiologically based pharmacokinetic (PBPK) model. Utilizing plasma concentration–time profiles of GZR derived from reported dose-escalation (50–800 mg) clinical studies and cumulative excretion data, around 10 parameters, including Michaelis constants (K_m) for OATP1B, CYP3A, and P-gp, were estimated via a cluster Gauss–Newton method (CGNM). Parameter combinations that could reproduce the clinical data of GZR were obtained; however, discrepancies were noted between the in vivo estimated K_m and the corresponding in vitro K_m. Next, by incorporating the in vitro K_m values into our PBPK–CGNM analyses utilizing a penalized parameter method, newly obtained parameter combinations appropriately reflected both the in vivo and in vitro observations. Particularly regarding OATP1B, while saturation of uptake was not clearly observed in the in vitro experiments without human serum albumin (HSA), K_m values capable of explaining in vivo saturation were obtained under physiological HSA concentrations. By estimating the extent of saturation for each molecule in the liver and intestine and conducting sensitivity analyses of the K_m values, it was inferred that OATP1B3 contributed the most to the nonlinearity of plasma GZR concentrations, followed by P-gp. In conclusion, the PBPK–CGNM, supplemented by penalized in vitro parameters, was shown to be effective for analyzing complex pharmacokinetics involving drug transporters and enzymes.