Pharmacokinetics of Venetoclax, a Novel BCL-2 Inhibitor, in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Non-Hodgkin Lymphoma
Pharmacokinetics of Venetoclax, a Novel BCL-2 Inhibitor, in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Non-Hodgkin Lymphoma
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DOI：
10.1002/jcph.821
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发表时间：
2017-04-01
影响因子：
2.9
通讯作者：
Wong, Shekman L.
中科院分区：
文献类型：
--
作者：
Salem, Ahmed Hamed;Agarwal, Suresh K.;Wong, Shekman L.
Venetoclax 是一种选择性 BCL-2 抑制剂，在美国被批准用于治疗 17p 缺失的慢性淋巴细胞白血病 (CLL) 患者，且这些患者之前至少接受过 1 次治疗。本分析的目的是表征血液恶性肿瘤患者血浆和尿液中的维奈托克药代动力学，并评估剂量比例、蓄积、弱和中度 CYP3A 抑制剂以及低脂肪和高脂肪膳食对维奈托克药代动力学的影响。患者每天服用一次 20 至 1200 毫克的维奈托克。使用非房室方法估计药代动力学参数。在低脂条件下，Venetoclax 的峰值暴露时间为 5 至 8 小时，不同剂量下的平均终末期消除半衰期为 14.1 至 18.2 小时。 Venetoclax 稳态暴露量显示出最小的积累，并在 300 至 900 mg 的剂量范围内按比例增加。低脂和高脂膳食使 Venetoclax 暴露量相对于禁食状态增加约 4 倍。中度 CYP3A 抑制剂使 Venetoclax 暴露量增加 40% 至 60%，而弱 CYP3A 抑制剂则没有影响。尿液中排泄的维奈托克量可忽略不计。总之，无论脂肪含量如何，venetoclax 的药代动力学特征都适合每天一次与食物一起服用。在 CLL 患者的 Venetoclax 起始阶段和加速阶段，应避免 Venetoclax 与中度 CYP3A 抑制剂同时使用，或减少 Venetoclax 剂量。肾排泄在维奈托克的消除中起最小作用。
Venetoclax is a selective BCL-2 inhibitor that is approved in the United States for the treatment of patients with chronic lymphocytic leukemia ( CLL) with 17p deletion who have received at least 1 prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors, as well as low-and high-fat meals on venetoclax pharmacokinetics. Patients received a once-daily venetoclax dose of 20 to 1200 mg. Pharmacokinetic parameters were estimated using noncompartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low-fat conditions, and the mean terminal-phase elimination half-life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady-state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low-fat and high-fat meals increased venetoclax exposures by approximately 4-fold relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60%, whereas weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once-daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp-up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax.