Abstract
Maribavir is in phase 3 clinical development for treatment of cytomegalovirus infection/disease in transplant recipients. Previous research, conducted using only intact cynomolgus monkeys, indicated biliary secretion as the primary elimination pathway for maribavir and that maribavir undergoes enterohepatic recirculation (EHR). To clarify the exact mechanisms of maribavir's EHR behavior, we studied its clearance pathways using intravenously administered 14C-labeled maribavir in intact and bile duct-cannulated (BDC) monkeys and constructed a semi-physiologically based pharmacokinetic (semi-PBPK) model. Total radioactivity metabolite profiles in plasma and excreta were quantitatively determined, along with plasma maribavir concentrations. Intact animals showed significantly lower clearance and longer half-lives in both total radioactivity and parent concentration in plasma than BDC monkeys. The primary in vitro and in vivo metabolic pathway for maribavir in monkey is direct glucuronidation; N-dealkylation and renal clearance are minor pathways. In BDC monkeys, 73% of dose was recovered as maribavir glucuronides in bile and 3% of dose was recovered as parent in bile and feces; in intact animals' feces, 58% of dose was recovered as parent and no glucuronides were detected. Therefore, EHR of maribavir occurs through biliary secretion of maribavir glucuronides, followed by hydrolysis of glucuronides in the gut lumen and subsequent reabsorption of parent. A semi-PBPK model, constructed from physiological, in vitro, and in vivo BDC monkey data, is capable of projecting maribavir's pharmacokinetic and EHR behavior in intact animals after intravenous or oral dosing, and could be applied to modeling other xenobiotics that are subject to similar EHR processes.
Significance Statement Through both mass balance and semi-physiologically based pharmacokinetic (semi-PBPK) modeling approaches, we mechanistically and quantitatively elucidated maribavir’s enterohepatic recirculation (EHR) behavior in monkeys, which occurs via extensive direct glucuronidation, biliary secretion of these glucuronides, luminal hydrolysis of glucuronides to parent, and subsequent reabsorption of the parent. We also identified important drug- and animal-specific parameters that determine the EHR kinetics, and the semi-PBPK model is readily applicable to other drugs that undergo similar metabolic and recirculation mechanisms.
- animal/nonclinical/preclinical
- metabolite disposition
- pharmacokinetics
- physiologically-based pharmacokinetic modeling/PBPK
- © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution CC BY License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.