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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a BCL-2 Inhibitor: Results of a Single- and Multiple-Dose Study
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Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a BCL-2 Inhibitor: Results of a Single- and Multiple-Dose Study

机译：利福平转运蛋白的转运抑制和CYP3A对威尼替肽药代动力学的诱导效应评估，BCL-2抑制剂：单剂量研究的结果

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摘要

Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. A single-dose and multiple-dose rifampin study was conducted to evaluate the effect of CYP3A induction and transporter inhibition on the pharmacokinetics of venetoclax. Subjects received a single dose of venetoclax 200 mg on day 1 of period 1 and days 1 and 14 of period 2, a single dose of rifampin 600 mg on day 1 of period 2, and rifampin 600 mg once daily on days 5 through 17 of period 2. Blood samples were collected up to 96 hours after each venetoclax dose on day 1 of period 1 and days 1 and 14 of period 2. Compared with venetoclax alone, coadministration with a single dose of rifampin increased venetoclax C-max and AUC by 106% (90%CI, 73%-145%) and 78% (90%CI, 50%-111%), respectively, whereas coadministration with multiple doses of rifampin decreased venetoclax C-max and AUC by 42% (90%CI, 31%-52%) and 71% (90%CI, 66%-76%), respectively. It was possible to isolate the net effect of chronic CYP3A induction from acute P-glycoprotein (P-gp) inhibition by comparing venetoclax exposures following coadministration with multiple doses of rifampin versus a single dose of rifampin, which showed that CYP3A induction decreased venetoclax C-max and AUC by 72% and 84%, respectively. These results are consistent with venetoclax being a P-gp substrate and indicate that CYP3A plays a major role in venetoclax metabolism. Prescribers should consider agents with little or no CYP3A induction during treatment with venetoclax.
机译：威尼柯克斯是一种选择性，有效的一类B细胞淋巴瘤-2抑制剂，其在各种血液恶性肿瘤中表现出临床疗效。进行单剂量和多剂量利福平研究，以评估CYP3A诱导和转运抑制对威尼替腊肠药代动力学的影响。受试者在第1天和第2天和第1天和第1天和第1天和第1天和第1天和第1天和第1天和第1天的一剂veretoclax 200mg的单剂量，每天第2天的600 mg，以及利福平600mg每日每日一次5到17天2.每天1天和第1天和第1天和第1天和第1天和第1天和第1天和第1天和第1天和第1天和第1天和第1天和第1天和第1天和2天的血液样品收集高达96小时的血液样品。单独使用venetoclax，用单剂量的利福平C-MAX和AUC的共同分子106％（90％CI，73％-145％）和78％（90％CI，50％-111％），而具有多剂量利福平的共同分子减少嘌呤菌C-MAX和AUC的42％（90％） CI，31％-52％）和71％（90％CI，66％-76％）。通过将venetoclax暴露在具有多剂量利福平之后与单剂量的利福平素相比，可以将慢性Cyp3a诱导从急性p-糖蛋白（p-gp）抑制抑制诱导抑制慢性Cyp3a抑制的净效应。最大和AUC分别为72％和84％。这些结果与venetoclax是p-GP底物的一致性，并表明CYP3A在威特科克克斯代谢中起主要作用。公章会应考虑在用嘌呤癌治疗期间考虑具有很少或没有CYP3A诱导的药剂。

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