Pharmacokinetic Evaluation of the Interaction between Hepatitis C Virus Protease Inhibitor Boceprevir and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Atorvastatin and Pravastatin
Pharmacokinetic Evaluation of the Interaction between Hepatitis C Virus Protease Inhibitor Boceprevir and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Atorvastatin and Pravastatin
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DOI：
10.1128/aac.02347-12
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发表时间：
2013-06-01
影响因子：
4.9
通讯作者：
Butterton, J. R.
中科院分区：
文献类型：
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作者：
Hulskotte, E. G. J.;Feng, H. -P.;Butterton, J. R.
博西普韦是一种强效口服丙型肝炎病毒抑制剂，也是一种强效、可逆的CYP 3A 4抑制剂，CYP 3A 4是许多3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂的主要代谢途径。因此，本研究的目的是研究阿托伐他汀或普伐他汀与博赛泼韦之间的药物相互作用。我们在20名健康成人志愿者中进行了一项单中心、开放标签、固定序列、单向交叉研究。受试者在第1天接受单剂量阿托伐他汀（40 mg）或普伐他汀（40 mg），随后接受boceprevir（800 mg，每日三次），持续7至10天。在存在稳态博赛泼维的情况下，重复单次给予阿托伐他汀或普伐他汀。在存在博赛泼维的情况下，阿托伐他汀暴露量增加，单次给药后阿托伐他汀从时间0至无穷大的浓度-时间曲线下面积（AUC（inf））增加2.3倍（90%置信区间[CI]，1.85，2.90），观察到的最大血浆浓度（C-max）增加2.7倍（90% CI，1.81，3.90）。在存在博赛泼韦的情况下，普伐他汀暴露量略有增加，普伐他汀AUC（inf）增加1.63倍（90% CI，1.03，2.58），C-max增加1.49倍（90% CI，1.03，2.14）。当药物与阿托伐他汀或普伐他汀联合给药时，博西普韦暴露量通常不变。所有不良事件均为轻度，与boceprevir已知的安全性特征一致。观察到的阿托伐他汀AUC增加130%支持在与博赛泼维联合给药时使用最低可能有效剂量的阿托伐他汀，而不超过最大日剂量40 mg。观察到与博赛泼维联合给药时普伐他汀AUC增加60%，这支持在密切临床监测的情况下，当与博赛泼维联合给药时，以推荐剂量开始普伐他汀治疗。
Boceprevir is a potent orally administered inhibitor of hepatitis C virus and a strong, reversible inhibitor of CYP3A4, the primary metabolic pathway for many 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Thus, the aim of the present study was to investigate drug-drug interactions between atorvastatin or pravastatin and boceprevir. We conducted a single-center, open-label, fixed-sequence, one-way-crossover study with 20 healthy adult volunteers. Subjects received single-dose atorvastatin (40 mg) or pravastatin (40 mg) on day 1, followed by boceprevir (800 mg three times daily) for 7 to 10 days. Repeat single doses of atorvastatin or pravastatin were administered in the presence of steady-state boceprevir. Atorvastatin exposure increased in the presence of boceprevir, with atorvastatin area under the concentration-time curve from time zero to infinity after single dosing (AUC(inf)) increasing 2.3-fold (90% confidence interval [CI], 1.85, 2.90) and maximum observed concentration in plasma (C-max) 2.7-fold (90% CI, 1.81, 3.90). Pravastatin exposure was slightly increased in the presence of boceprevir, with pravastatin AUC(inf) increasing 1.63-fold (90% CI, 1.03, 2.58) and C-max 1.49-fold (90% CI, 1.03, 2.14). Boceprevir exposure was generally unchanged when the drug was coadministered with atorvastatin or pravastatin. All adverse events were mild and consistent with the known safety profile of boceprevir. The observed 130% increase in AUC of atorvastatin supports the use of the lowest possible effective dose of atorvastatin when coadministered with boceprevir, without exceeding a maximum daily dose of 40 mg. The observed 60% increase in pravastatin AUC with boceprevir coadministration supports the initiation of pravastatin treatment at the recommended dose when coadministered with boceprevir, with close clinical monitoring.