Population Pharmacokinetic Analyses for Belzutifan to Inform Dosing Considerations and Labeling
AbstractBelzutifan (Welireg, Merck& Co, Inc.) is an oral, potent inhibitor of hypoxia-inducible factor (HIF) 2 α, 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 (pNET). It is primarily metabolized by the polymorphic uridine 5'-diphospho-glucuronosyltransf erase (UGT) 2B17 and cytochrome (CYP) 2C19. A population pharmacokinetic (PK) model was built, using NONMEM® v7.3, based on demographics/PK data from 3 clinical pharmacology (food effect, formulation bridging, genotype/race effect) and 2 clinical (phase 1 dose escalation/expansion in RCC and other solid tumors; phase 2 in VHL patients) studies. 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 2-compartment model with first-order absorption and elimination. For VHL patients, the predicted geometric mean (% coefficient of variation [CV]) apparent clearance (CL/F) was 7.3 L/hr (51%), apparent total volume of distribution (Vd/F) was 130 L (35%); and half-life was 12.39 hours (42%). There were no clinically relevant differences in belzutifan PK based on the individual covariate s of age, sex, ethnicity, race, body weight, mild/moderate renal impairment, or mild hepatic impairment. In this model dual UGT2B17 and CYP2C19 poor metabolizers (PM) were estimated to ha...
Source: CPT: Pharmacometrics and Systems Pharmacology - Category: Drugs & Pharmacology Authors: Dhananjay D. Marathe,
Petra M. Jauslin,
Huub Jan Kleijn,
Carolina de Miranda Silva,
Anne Chain,
Thomas Bateman,
Peter M. Shaw,
Anson K. Abraham,
Eunkyung A. Kauh,
Yanfang Liu,
Rodolfo F. Perini,
Dinesh P. de Alwis,
Lokesh Jain Tags: ARTICLE Source Type: research
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