دورية أكاديمية
Exposure-Response Analyses for Belzutifan to Inform Dosing Considerations and Labeling.
| العنوان: | Exposure-Response Analyses for Belzutifan to Inform Dosing Considerations and Labeling. |
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| المؤلفون: | Marathe DD; Merck & Co., Inc., Rahway, NJ, USA., Jauslin PM; Certara, Princeton, NJ, USA., Jan Kleijn H; Certara, Princeton, NJ, USA., De Miranda Silva C; Merck & Co., Inc., Rahway, NJ, USA., Chain A; Merck & Co., Inc., Rahway, NJ, USA., Abraham AK; Merck & Co., Inc., Rahway, NJ, USA., Kauh EA; Merck & Co., Inc., Rahway, NJ, USA., Liu Y; Merck & Co., Inc., Rahway, NJ, USA., Perini RF; Merck & Co., Inc., Rahway, NJ, USA., Alwis DP; Merck & Co., Inc., Rahway, NJ, USA., Jain L; Merck & Co., Inc., Rahway, NJ, USA. |
| المصدر: | Journal of clinical pharmacology [J Clin Pharmacol] 2024 May 16. Date of Electronic Publication: 2024 May 16. |
| Publication Model: | Ahead of Print |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wiley Country of Publication: England NLM ID: 0366372 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4604 (Electronic) Linking ISSN: 00912700 NLM ISO Abbreviation: J Clin Pharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2013- : Oxford : Wiley Original Publication: Stamford, Conn., Hall Associates. |
| مستخلص: | 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. (© 2024 Merck Sharp & Dohme LLC. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.) |
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| فهرسة مساهمة: | Keywords: benefit–risk; exposure–response; modeling; pharmacokinetics |
| تواريخ الأحداث: | Date Created: 20240516 Latest Revision: 20240516 |
| رمز التحديث: | 20240516 |
| DOI: | 10.1002/jcph.2459 |
| PMID: | 38752556 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1552-4604 |
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| DOI: | 10.1002/jcph.2459 |