Effects of oral posaconazole on the pharmacokinetics of sirolimus
Effects of oral posaconazole on the pharmacokinetics of sirolimus
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DOI：
10.1185/03007990802644209
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发表时间：
2009-03-01
影响因子：
2.3
通讯作者：
McLeod, James
中科院分区：
文献类型：
--
作者：
Moton, Allen;Ma, Lei;McLeod, James
目的：唑类抗真菌剂通常与免疫抑制剂共同给予实体器官和造血干细胞移植的受者。泊沙康唑是一种广谱三唑，是细胞色素P450（CYP）同工酶CYP3A4的抑制剂，西罗莫司是一种免疫抑制剂，是该酶的底物。我们评估了泊沙康唑对西罗莫司药代动力学的影响，在一个开放标签，多阶段，药物相互作用study.Methods：12名健康受试者接受了一个剂量的西罗莫司2毫克的第1天。在28天的洗脱期后，受试者接受泊沙康唑400 mg bid治疗16天（至第45天）。第36天，西罗莫司2 mg和泊沙康唑400 mg联合给药。在第1天和第36天给药后216小时内采集血样，以测定西罗莫司血浆浓度，并计算血浆药代动力学参数。采用单因素方差分析评价药物相互作用。平均（%变异系数）最大血浆浓度（C-max）和西罗莫司曲线下面积（AUC）在第1天分别为4.9 ng/mL（38）和145 h中心点ng/mL（45），分别。这些增加与泊沙康唑对CYP3A4的抑制作用一致。不良事件报告的5名受试者（42%）接受泊沙康唑和西罗莫司和3（25%）和8（67%）的受试者接受泊沙康唑仅在第30天至35天（presirolimus）和第37天至45天（postsirolimus），分别：由于泊沙康唑有临床相关的影响西罗莫司暴露，代理商可能不应该共同管理。虽然这是一项描述性研究，但一个潜在的限制是样本量小。如果参加研究的人数更多，结论可能会更有力。
Objectives: Azole antifungal agents are often coadministered with immunosuppressants to recipients of solid organ and hematopoietic stem cell transplants. Posaconazole, an extended-spectrum triazole, is an inhibitor of the cytochrome P450 (CYP) isoenzyme CYP3A4, and sirolimus, an immunosuppressant, is a substrate of the enzyme. We evaluated the effects of posaconazole on sirolimus pharmacokinetics in an open-label, multiperiod, drug-interaction study.Methods: Twelve healthy subjects received one dose of sirolimus 2 mg on day 1. After a 28-day washout period, subjects received posaconazole 400 mg bid for 16 days (to day 45). On day 36, sirolimus 2 mg and posaconazole 400 mg were coadministered. Blood samples to determine sirolimus plasma concentrations were collected up to 216 hours post dose on days 1 and 36 and plasma pharmacokinetic parameters were calculated. Drug interactions were evaluated using one-way analysis of variance. Mean (% coefficient of variation) maximum plasma concentration (C-max) and area under the curve (AUC) of sirolimus at day 1 were 4.9 ng/mL (38) and 145 h center dot ng/mL (45), respectively.Results: Coadministration with posaconazole increased sirolimus Cmax and AUC by 6.7- and 8.9-fold, respectively. These increases are consistent with CYP3A4 inhibition by posaconazole. Adverse events were reported by five subjects (42%) receiving posaconazole and sirolimus and by three (25%) and eight (67%) subjects receiving posaconazole only on days 30 to 35 (presirolimus) and days 37 to 45 (postsirolimus), respectively.Conclusion: Because posaconazole has a clinically relevant effect on sirolimus exposure, the agents should probably not be coadministered. Although this was a descriptive study, one potential limitation was the small sample size. The conclusion could have been made stronger if the number of people enrolled in the study had been greater.