LAUSR

Regorafenib, a multikinase inhibitor used in the treatment of various solid tumors, undergoes extensive uridine 5′‐diphosphate glucuronosyltransferase (Ugt)1a9‐mediated glucuronidation to form regorafenib‐N‐β‐glucuronide (M7; RG), but the contribution of hepatic uptake transporters, such as organic anion‐transporting polypeptide (Oatp)1b2, to the pharmacokinetics of regorafenib remains poorly understood. Using NONMEM‐based, population‐based, parent‐metabolite modeling, we found that Oatp1b2 and sex strongly impact the systemic exposure to RG in mice receiving oral regorafenib. Metabolic studies revealed that the liver microsomal expression of cytochrome P450 (Cyp)3a11 is twofold lower in female mice, whereas Ugt1a9 levels and function are not sex dependent. This finding is consistent with the metabolism of regorafenib occurring via two competing pathways, and the lack of Oatp1b2 results in decreased clearance of RG. The described model provides mechanistic insights into the in vivo disposition of regorafenib.