Effect of Telaprevir on the Pharmacokinetics of Cyclosporine and Tacrolimus
Effect of Telaprevir on the Pharmacokinetics of Cyclosporine and Tacrolimus
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DOI：
10.1002/hep.24443
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发表时间：
2011-07-01
期刊：
影响因子：
13.5
通讯作者：
Luo, Xia
中科院分区：
文献类型：
--
作者：
Garg, Varun;van Heeswijk, Rolf;Luo, Xia
丙型肝炎病毒蛋白酶抑制剂telaprevir是细胞色素P450 3A酶的抑制剂，负责环孢素和他克莫司的代谢。这项I期、开放标签、非随机、单序列研究评估了特拉匹韦联合给药对单剂量环孢素或他克莫司药动学的影响，在两个独立的小组中，每个小组由10名健康志愿者组成。在A部分中，环孢素单次口服剂量为100 mg，随后至少8天洗脱期，随后单次口服10 mg环孢素与单次特拉韦（750 mg）或与稳态特拉韦（750 mg / 8小时[q8h]）联合给药。在B部分中，他克莫司单独口服2 mg单剂量，然后是至少14天的洗脱期，随后他克莫司单剂量0.5 mg与稳态泰拉韦（750 mg q8h）联合给药。与稳态特拉匹韦共给药使环孢素剂量标准化（DN）暴露（DN_AUC（0-无穷大））增加约4.6倍，使他克莫司DN_AUC（0-无穷大）增加约70倍。与特拉匹韦共给药使环孢素的终末消除半衰期（t(1/2)）从平均（标准差[SD]） 12（1.67）小时增加到42.1（11.3）小时，他克莫司的终末消除半衰期（t(1/2)）从平均（SD） 40.7（5.85）小时增加到196（159）小时。结论：在本研究中，特拉匹韦使环孢素和他克莫司的血药浓度均显著升高，可能导致严重或危及生命的不良事件。特拉匹韦尚未在器官移植患者中进行研究；不建议在这些患者中使用，因为尚未完成所需的研究，以了解与环孢素或他克莫司安全联合给药所需的适当剂量调整，并且尚未获得监管部门的批准。(肝脏病学2011;54:20-27)
The hepatitis C virus protease inhibitor telaprevir is an inhibitor of the enzyme cytochrome P450 3A, responsible for the metabolism of both cyclosporine and tacrolimus. This Phase I, open-label, nonrandomized, single-sequence study assessed the effect of telaprevir coadministration on the pharmacolcinetics of a single dose of either cyclosporine or tacrolimus in two separate panels of 10 healthy volunteers each. In Part A, cyclosporine was administered alone as a single 100-mg oral dose, followed by a minimum 8-day washout period, and subsequent coadministration of a single 10-mg oral dose of cyclosporine with either a single dose of telaprevir (750 mg) or with steady-state telaprevir (750 mg every 8 hours [q8h]). In Part B, tacrolimus was administered alone as a single 2-mg oral dose, followed by a minimum 14-day washout period, and subsequent coadministration of a single 0.5-mg dose of tacrolimus with steady-state telaprevir (750 mg q8h). Coadministration with steady-state telaprevir increased cyclosporine dose-normalized (DN) exposure (DN_AUC(0-infinity)) by approximately 4.6-fold and increased tacrolimus DN_AUC(0-infinity) by approximately 70-fold. Coadministration with telaprevir increased the terminal elimination half-life (t(1/2)) of cyclosporine from a mean (standard deviation [SD]) of 12 (1.67) hours to 42.1 (11.3) hours and t(1/2), of tacrolimus from a mean (SD) of 40.7 (5.85) hours to 196 (159) hours. Conclusion: In this study, telaprevir increased the blood concentrations of both cyclosporine and tacrolimus significantly, which could lead to serious or life-threatening adverse events. Telaprevir has not been studied in organ transplant patients; its use in these patients is not recommended because the required studies have not been completed to understand appropriate dose adjustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory approval has not been obtained. (HEPATOLOGY 2011;54:20-27)