Khatri Amit, Dutta Sandeep, Dunbar Martin, Podsadecki Thomas, Trinh Roger, Awni Walid, Menon Rajeev
AbbVie, Inc., Research and Development, North Chicago, Illinois, USA
AbbVie, Inc., Research and Development, North Chicago, Illinois, USA.
Antimicrob Agents Chemother. 2016 Apr 22;60(5):2965-71. doi: 10.1128/AAC.02605-15. Print 2016 May.
The three direct-acting antiviral agent (3D) regimen is a novel combination of direct-acting antiviral agents (DAAs) that has proven effective for the treatment of hepatitis C virus (HCV) infection. Given the potential for coadministration in patients with human immunodeficiency virus infection, possible drug interactions with antiretroviral drugs must be carefully considered. Four phase 1, multiple-dose pharmacokinetic studies were conducted in healthy volunteers (n = 66). The 3D regimen of 150/100 mg daily paritaprevir/ritonavir, 25 mg daily ombitasvir, and 400 mg twice-daily dasabuvir was administered alone or in combination with 200 mg daily of emtricitabine and 300 mg daily of tenofovir disoproxil fumarate (tenofovir DF), 25 mg daily of rilpivirine, or 400 mg of raltegravir twice daily. A 2-DAA regimen of 150/100 mg daily paritaprevir/ritonavir and 400 mg of dasabuvir twice daily was also studied in combination with efavirenz/emtricitabine/tenofovir DF at 600/200/300 mg daily, respectively (Atripla; Bristol-Myers Squibb). Pharmacokinetic parameters were determined from plasma drug concentrations. No clinically significant drug interactions were observed (≤32% change in exposure) between the 3D regimen and that of emtricitabine plus tenofovir DF. Raltegravir exposure was increased up to 134% when the drug was coadministered with the 3D regimen. Although coadministration with rilpivirine was well tolerated in healthy volunteers, observed elevations in rilpivirine exposures may increase the potential for adverse drug reactions. Concomitant use of the 2-DAA regimen and efavirenz/emtricitabine/tenofovir DF was discontinued owing to poor tolerability and adverse events. No dose adjustment is required during coadministration of raltegravir, tenofovir DF, or emtricitabine with the 3D regimen. Rilpivirine is not recommended and efavirenz is contraindicated for coadministration with the 3D regimen.
三联直接抗病毒药物（3D）方案是一种新型的直接抗病毒药物（DAA）组合，已被证明对丙型肝炎病毒（HCV）感染的治疗有效。鉴于其在人类免疫缺陷病毒感染患者中可能存在联合用药情况，必须仔细考虑与抗逆转录病毒药物之间可能的药物相互作用。在健康志愿者（n = 66）中进行了四项1期多剂量药代动力学研究。150/100毫克每日的帕立普韦/利托那韦、25毫克每日的奥比他韦和400毫克每日两次的达沙布韦组成的3D方案单独给药，或与200毫克每日的恩曲他滨和300毫克每日的替诺福韦酯富马酸盐（替诺福韦DF）、25毫克每日的利匹韦林或400毫克每日两次的拉替拉韦联合给药。还研究了150/100毫克每日的帕立普韦/利托那韦和400毫克每日两次的达沙布韦组成的二联DAA方案与依非韦伦/恩曲他滨/替诺福韦DF（分别为600/200/300毫克每日；商品名：Atripla；百时美施贵宝公司）联合使用的情况。根据血浆药物浓度确定药代动力学参数。在3D方案与恩曲他滨加替诺福韦DF之间未观察到具有临床意义的药物相互作用（暴露量变化≤32%）。当拉替拉韦与3D方案联合给药时，其暴露量增加高达134%。虽然在健康志愿者中联合使用利匹韦林耐受性良好，但观察到的利匹韦林暴露量升高可能会增加药物不良反应的可能性。由于耐受性差和不良事件，二联DAA方案与依非韦伦/恩曲他滨/替诺福韦DF的联合使用已停止。在拉替拉韦、替诺福韦DF或恩曲他滨与3D方案联合给药期间无需调整剂量。不推荐利匹韦林与3D方案联合使用，依非韦伦与3D方案联合使用为禁忌。
