Management of Venetoclax-Posaconazole Interaction in Acute Myeloid Leukemia Patients: Evaluation of Dose Adjustments
Management of Venetoclax-Posaconazole Interaction in Acute Myeloid Leukemia Patients: Evaluation of Dose Adjustments
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DOI：
10.1016/j.clinthera.2017.01.003
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发表时间：
2017-02-01
影响因子：
3.2
通讯作者：
Salem, Ahmed Hamed
中科院分区：
文献类型：
--
作者：
Agarwal, Suresh K.;DiNardo, Courtney D.;Salem, Ahmed Hamed
目的：研究泊沙康唑对急性髓系白血病患者细胞色素P450 3A(CyP3A)抑制剂泊沙康唑的药代动力学特性的影响，以确定控制这种潜在相互作用所需的剂量调整。方法：12例患者在第1~5天口服维奈替克20~200 mg，静脉滴注地西他滨20 mg/m(2)，第6~20天单用维奈替克400 mg，第1~5天静脉注射地西他滨20 mg/m~2。第21~28天，患者接受300毫克泊沙康唑和减少剂量的万乃馨(50或100毫克)，以解释预期的万乃馨血药浓度增加。分别于给药前及给药后24小时采集血样。结果：与单用400 mg静脉滴注(第20天)相比，50 mg静脉滴注与多剂量泊沙康唑合用使平均静脉滴注C-max和AUC(0-24)分别增加53%和76%，而静脉滴注100 mg与泊沙康唑合用使平均静脉滴注Cmax和AUC(0-24)分别增加93%和155%。校正不同剂量和非线性因素后，泊沙康唑的Cmax和AUC(0-24)分别增加7.1倍和8.8倍。泊沙康唑50毫克和100毫克静脉滴注的耐受性都很好。(C)2017 Elsevier HS Journal，Inc.保留所有权利。
Purpose: The effect of posaconazole, a strong cytochrome P450 3A (CYP3A) inhibitor and commonly used antifungal agent, on the pharmacokinetic properties of venetoclax, a CYP3A substrate, was evaluated in patients with acute myeloid leukemia to determine the dose adjustments needed to manage this potential interaction.Methods: Twelve patients received 20- to 200-mg ramp-up treatment with oral venetoclax and 20 mg/m(2) of intravenous decitabine on days 1 through 5, followed by 400 mg of venetoclax alone on days 6 through 20. On days 21 through 28, patients received 300 mg of posaconazole plus reduced doses of venetoclax (50 or 100 mg) to account for expected increases in venetoclax plasma concentrations. Blood samples were collected before dosing and up to 24 hours after the venetoclax dose on days 20 and 28.Findings: Compared with a venetoclax dose of 400 mg when administered alone (day 20), coad-ministration of venetoclax at a 50-mg dose with multiple doses of posaconazole increased mean venetoclax C-max and AUC(0-24) by 53% and 76%, respectively, whereas coad-ministration of venetoclax at a 100-mg dose with posaconazole increased mean venetoclax Cmax and AUC(0-24) by 93% and 155%, respectively. When adjusted for different doses and nonlinearity, posaconazole was estimated to increase venetoclax Cmax and AUC(0-24) by 7.1 and 8.8-fold, respectively. Both the 50- and 100-mg venetoclax doses administered with posaconazole were well tolerated. (C) 2017 Elsevier HS Journals, Inc. All rights reserved.