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Exposure-Response Analyses for Belzutifan to Inform Dosing Considerations and Labeling.
- Source :
-
Journal of clinical pharmacology [J Clin Pharmacol] 2024 Oct; Vol. 64 (10), pp. 1246-1258. Date of Electronic Publication: 2024 May 16. - Publication Year :
- 2024
-
Abstract
- Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent hypoxia-inducible factor-2α inhibitor, recently approved in the United States for the treatment of von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) and other VHL disease-associated neoplasms. Safety and efficacy were investigated in two clinical studies: a Phase 1 dose escalation/expansion study in solid tumors and RCC and a Phase 2 study in VHL-RCC. A population pharmacokinetic model was used to estimate belzutifan exposures to facilitate exposure-response (E-R) analyses for efficacy and safety endpoints. Relationships between exposure and efficacy (overall response rate, disease control rate, progression-free survival, best overall tumor size response, and other endpoints), safety outcomes (Grade ≥3 anemia, Grade ≥3 hypoxia, and time to first dose reduction/dose interruption), and pharmacodynamic biomarkers (erythropoietin [EPO] and hemoglobin [Hgb]) were evaluated using various regression techniques and time-to-event analyses. Efficacy E-R was generally flat with non-significant positive trends with exposure. The safety E-R analyses demonstrated a lack of relationship for Grade ≥3 hypoxia and a positive relationship for Grade ≥3 anemia, with incidences also significantly dependent on baseline Hgb. Exposure-dependent reductions in EPO and Hgb were observed. Based on the cumulative benefit-risk assessment in VHL disease-associated neoplasms using E-R, no a priori dose adjustment is recommended for any subpopulation. These analyses supported the benefit-risk profile of belzutifan 120 mg once daily dosing in patients with VHL-RCC for labeling and the overall development program.<br /> (© 2024 Merck Sharp & Dohme LLC. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
- Subjects :
- Humans
Female
Male
Middle Aged
Adult
Kidney Neoplasms drug therapy
Aged
Drug Labeling
von Hippel-Lindau Disease drug therapy
Antineoplastic Agents pharmacokinetics
Antineoplastic Agents administration & dosage
Antineoplastic Agents adverse effects
Antineoplastic Agents therapeutic use
Erythropoietin administration & dosage
Erythropoietin pharmacokinetics
Basic Helix-Loop-Helix Transcription Factors antagonists & inhibitors
Models, Biological
Hemoglobins analysis
Dose-Response Relationship, Drug
Carcinoma, Renal Cell drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4604
- Volume :
- 64
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of clinical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 38752556
- Full Text :
- https://doi.org/10.1002/jcph.2459