Population pharmacokinetic analyses for belzutifan to inform dosing considerations and labeling

Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent inhibitor of hypoxia-inducible factor 2α, approved for the treatment of certain patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors. It is primarily metabolized by the polymorphic uridine 5'-diphospho-glucuronosyltransferase (UGT) 2B17 and cytochrome (CYP) 2C19. A population pharmacokinetic (PK) model was built, using NONMEM version 7.3, based on demographics/PK data from three clinical pharmacology (food effect, formulation bridging, and genotype/race effect) and two clinical studies (phase I dose escalation/expansion in patients with RCC and other solid tumors; phase II in patients with VHL). Median (range) age for the combined studies was 55 years (19-84) and body weight was 73.6 kg (42.1-165.8). Belzutifan plasma PK was well-characterized by a linear two-compartment model with first-order absorption and elimination. For patients with VHL, the predicted geometric mean (% coefficient of variation) apparent clearance was 7.3 L/h (51%), apparent total volume of distribution was 130 L (35%), and half-life was 12.39 h (42%). There were no clinically relevant differences in belzutifan PK based on the individual covariates of age, sex, ethnicity, race, body weight, mild/moderate renal impairment, or mild hepatic impairment. In this model, dual UGT2B17 and CYP2C19 poor metabolizers (PMs) were estimated to have a 3.2-fold higher area under the plasma concentration-time curve compared to UGT2B17 extensive metabolizer and CYP2C19 non-PM patients. This population PK analysis enabled an integrated assessment of PK characteristics with covariate effects in the overall population and subpopulations for belzutifan labeling.