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 Oct; Vol. 64 (10), pp. 1246-1258. Date of Electronic Publication: 2024 May 16. |
نوع المنشور: | Journal Article; Clinical Trial, Phase II; Clinical Trial, Phase I |
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. |
مواضيع طبية MeSH: | Dose-Response Relationship, Drug* , Carcinoma, Renal Cell*/drug therapy, 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 |
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.) |
References: | Deeks ED. Belzutifan: first approval. Drugs. 2021;81:1921‐1927. doi:10.1007/s40265‐021‐01606‐x. Cowey CL, Rathmell WK. VHL gene mutations in renal cell carcinoma: role as a biomarker of disease outcome and drug efficacy. Curr Oncol Rep. 2009;11:94‐101. doi:10.1007/s11912‐009‐0015‐5. Choueiri TK, Bauer TM, Papadopoulos KP, et al. Inhibition of hypoxia‐inducible factor‐2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021;27:802‐805. doi:10.1038/s41591‐021‐01324‐7. Hasanov E, Jonasch E. MK‐6482 as a potential treatment for von Hippel‐Lindau disease‐associated clear cell renal cell carcinoma. Expert Opin Investig Drugs. 2021;30:495‐504. doi:10.1080/13543784.2021.1925248. U.S. Food and Drug Adminstration. Belzutifan Prescribing information. 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215383s000lbl.pdf. Fallah J, Brave MH, Weinstock C, et al. FDA approval summary: belzutifan for von Hippel‐Lindau disease‐associated tumors. Clin Cancer Res. 2022;28:4843‐4848. doi:10.1158/1078‐0432.Ccr‐22‐1054. Xu R, Wang K, Rizzi JP, et al. 3‐[(1S,2S,3R)‐2,3‐Difluoro‐1‐hydroxy‐7‐methylsulfonylindan‐4‐yl]oxy‐5‐fluorobenzonitrile (PT2977), a Hypoxia‐inducible factor 2α (HIF‐2α) inhibitor for the treatment of clear cell renal cell carcinoma. J Med Chem. 2019;62:6876‐6893. doi:10.1021/acs.jmedchem.9b00719. Marathe DD, Jauslin PM, Kleijn HJ, et al. Population pharmacokinetic analyses for belzutifan to inform dosing considerations and labeling. CPT Pharmacometrics Syst Pharmacol. 2023;12:1499‐1510. doi:10.1002/psp4.13028. Haase VH. Regulation of erythropoiesis by hypoxia‐inducible factors. Blood Rev. 2013;27:41‐53. doi:10.1016/j.blre.2012.12.003. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel‐Lindau disease. N Engl J Med. 2021;385:2036‐2046. doi:10.1056/NEJMoa2103425. Kawakatsu S, Bruno R, Kågedal M, et al. Confounding factors in exposure‐response analyses and mitigation strategies for monoclonal antibodies in oncology. Br J Clin Pharmacol. 2021;87:2493‐2501. doi:10.1111/bcp.14662. |
فهرسة مساهمة: | Keywords: benefit–risk; exposure–response; modeling; pharmacokinetics |
المشرفين على المادة: | 0 (Antineoplastic Agents) 11096-26-7 (Erythropoietin) 0 (Basic Helix-Loop-Helix Transcription Factors) 1B37H0967P (endothelial PAS domain-containing protein 1) 0 (Hemoglobins) |
تواريخ الأحداث: | Date Created: 20240516 Date Completed: 20240927 Latest Revision: 20240927 |
رمز التحديث: | 20240927 |
DOI: | 10.1002/jcph.2459 |
PMID: | 38752556 |
قاعدة البيانات: | MEDLINE |
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