Yan Yuting, Guo Yujiao, Wang Ziyi, He Wei, Zhu Yu, Zhao Xiaoli, Sun Luning, Wang Yongqing
Research Division of Clinical Pharmacology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China.
Department of Hematology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China.
Curr Drug Metab. 2025;25(8):564-575. doi: 10.2174/0113892002338926241114080504.
Venetoclax is a first-in-class B-cell lymphoma/lymphoma-2 (BCL-2) inhibitor that induces apoptosis in malignant cells through the inhibition of BCL-2. The clinical response to venetoclax exhibits heterogeneity, and its sensitivity and resistance may be intricately linked to genetic expression. Pharmacokinetic studies following doses of venetoclax (ranging from 100 to 1200mg) revealed a time to maximum observed plasma concentration of 5-8 hours, with a maximum blood concentration of 1.58-3.89 μg/mL, and a 24-hour area under the concentration-time curve of 12.7-62.8 μg·h/mL. Population-based pharmacokinetic investigations highlighted that factors such as low-fat diet, race, and severe hepatic impairment play pivotal roles in influencing venetoclax dose selection. Being a substrate for CYP3A4, P-glycoprotein, and breast cancer resistance protein, venetoclax undergoes primary metabolism and clearance in the liver, displaying low accumulation in the body.The significance of dose modifications (a 50% decrease with moderate and a 75% reduction with strong CYP3A inhibitors) and a cautious two-hour interval when co-administered with P-glycoprotein inhibitors are highlighted by insights from clinical medication interaction studies. Moreover, an exposure-response relationship analysis indicates that venetoclax exposure significantly correlates not only with overall survival and total response rate but also with the occurrence of ≥ 3-grade neutropenia. In real-world studies, common or severe side effects of venetoclax include tumor lysis syndrome, myelosuppression, nausea, diarrhea, constipation, infection, autoimmune hemolytic anemia, and cardiac toxicity, among others. In this review, we summarize the current clinical pharmacology studies and side effects of venetoclax, which showed that the approved dosage of venetoclax is relatively wide, and the dosage for different hematologic populations can be streamlined in the future.
维奈克拉是一流的B细胞淋巴瘤/白血病-2（BCL-2）抑制剂，通过抑制BCL-2诱导恶性细胞凋亡。维奈克拉的临床反应存在异质性，其敏感性和耐药性可能与基因表达密切相关。给予维奈克拉（剂量范围为100至1200mg）后的药代动力学研究显示，达到最大观察血浆浓度的时间为5至8小时，最大血药浓度为1.58至3.89μg/mL，浓度-时间曲线下24小时面积为12.7至62.8μg·h/mL。基于人群的药代动力学研究强调，低脂饮食、种族和严重肝功能损害等因素在影响维奈克拉剂量选择方面起着关键作用。作为细胞色素P450 3A4（CYP3A4）、P-糖蛋白和乳腺癌耐药蛋白的底物，维奈克拉在肝脏中进行主要代谢和清除，在体内蓄积较少。临床药物相互作用研究的见解突出了剂量调整（与中度CYP3A抑制剂合用时降低50%，与强效CYP3A抑制剂合用时降低75%）以及与P-糖蛋白抑制剂合用时谨慎的两小时间隔的重要性。此外，暴露-反应关系分析表明，维奈克拉暴露不仅与总生存期和总缓解率显著相关，还与≥3级中性粒细胞减少的发生相关。在真实世界研究中，维奈克拉常见或严重的副作用包括肿瘤溶解综合征、骨髓抑制、恶心、腹泻、便秘、感染、自身免疫性溶血性贫血和心脏毒性等。在本综述中，我们总结了维奈克拉目前的临床药理学研究和副作用，结果表明维奈克拉的批准剂量范围相对较宽，未来不同血液学人群的剂量可进一步优化。
