Merck & Co., Inc., Kenilworth, New Jersey, USA
Merck & Co., Inc., Kenilworth, New Jersey, USA.
Antimicrob Agents Chemother. 2019 Apr 25;63(5). doi: 10.1128/AAC.02016-18. Print 2019 May.
Identifying and understanding potential drug-drug interactions (DDIs) are vital for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This article discusses DDIs between doravirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), and cytochrome P450 3A (CYP3A) substrates and drugs that modulate CYP3A activity. Consistent with previously published data and DDI trials with the CYP3A substrates midazolam and atorvastatin, doravirine did not have any meaningful impact on the pharmacokinetics of the CYP3A substrates ethinyl estradiol and levonorgestrel. Coadministration of doravirine with CYP3A inhibitors (ritonavir or ketoconazole) increased doravirine exposure approximately 3-fold. However, these increases were not considered clinically meaningful. Conversely, previously published trials showed that coadministered CYP3A inducers (rifampin and rifabutin) decreased doravirine exposure by 88% and 50%, respectively (K. L. Yee, S. G. Khalilieh, R. I. Sanchez, R. Liu, et al., Clin Drug Investig 37:659-667, 2017 [https://doi.org/10.1007/s40261-017-0513-4]; S. G. Khalilieh, K. L. Yee, R. I. Sanchez, R. Liu, et al., J Clin Pharmacol 58:1044-1052, 2018 [https://doi.org/10.1002/jcph.1103]), while doravirine exposure following prior efavirenz administration led to an initial reduction in doravirine exposure of 62%, but the reduction became less pronounced with time (K. L. Yee, R. I. Sanchez, P. Auger, R. Liu, et al., Antimicrob Agents Chemother 61:e01757-16, 2017 [https://doi.org/10.1128/AAC.01757-16]). Overall, the coadministration of doravirine with CYP3A inhibitors and substrates is, therefore, supported by these data together with efficacy and safety data from clinical trials, while coadministration with strong CYP3A inducers, such as rifampin, cannot be recommended. Concomitant dosing with rifabutin (a CYP3A inducer less potent than rifampin) is acceptable if doravirine dosing is adjusted from once to twice daily; however, the effect of other moderate inducers on doravirine pharmacokinetics is unknown.
识别和了解潜在的药物-药物相互作用（DDI）对于治疗人类免疫缺陷病毒 1 型（HIV-1）感染至关重要。本文讨论了多替拉韦（一种非核苷类逆转录酶抑制剂（NNRTI））与细胞色素 P450 3A（CYP3A）底物和调节 CYP3A 活性的药物之间的 DDI。与先前发表的数据和 CYP3A 底物咪达唑仑和阿托伐他汀的 DDI 试验一致，多替拉韦对 CYP3A 底物炔雌醇和左炔诺孕酮的药代动力学没有任何有意义的影响。多替拉韦与 CYP3A 抑制剂（利托那韦或酮康唑）联合使用可使多替拉韦暴露量增加约 3 倍。然而，这些增加被认为没有临床意义。相反，先前发表的试验表明，同时使用 CYP3A 诱导剂（利福平利福布汀）分别使多替拉韦的暴露量减少了 88%和 50%（K. L. Yee、S. G. Khalilieh、R. I. Sanchez、R. Liu 等人，Clin Drug Investig 37:659-667，2017[https://doi.org/10.1007/s40261-017-0513-4]；S. G. Khalilieh、K. L. Yee、R. I. Sanchez、R. Liu 等人，J Clin Pharmacol 58:1044-1052，2018[https://doi.org/10.1002/jcph.1103]），而多替拉韦在依非韦伦给药后的暴露量最初减少了 62%，但随着时间的推移，减少幅度变得不那么明显（K. L. Yee、R. I. Sanchez、P. Auger、R. Liu 等人，Antimicrob Agents Chemother 61:e01757-16，2017[https://doi.org/10.1128/AAC.01757-16]）。总的来说，这些数据以及临床试验的疗效和安全性数据支持多替拉韦与 CYP3A 抑制剂和底物联合使用，而与强 CYP3A 诱导剂（如利福平）联合使用则不能推荐。如果将多替拉韦的剂量从每日一次调整为每日两次，同时使用较弱的 CYP3A 诱导剂利福布汀（比利福平稍弱的 CYP3A 诱导剂）是可以接受的；然而，其他中度诱导剂对多替拉韦药代动力学的影响尚不清楚。
