Elucidation of Metabolic and Disposition Pathways for Maribavir in Nonhuman Primates through Mass Balance and Semi–Physiologically Based Modeling Approaches

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 (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, and this is followed by hydrolysis of glucuronides in the gut lumen and subsequent reabsorption of parent. A semi-PBPK model constructed from physiologic, 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.