Merck & Co., Inc., Kenilworth, New Jersey, USA
Merck & Co., Inc., Kenilworth, New Jersey, USA.
Antimicrob Agents Chemother. 2019 Mar 27;63(4). doi: 10.1128/AAC.02142-18. Print 2019 Apr.
The combination of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir-boosted HIV protease inhibitors in three phase 1 trials. Drug-drug interaction trials with healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir (= 10) and the potential two-way pharmacokinetic interactions of elbasvir (= 30) or grazoprevir (= 39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir. Coadministration of ritonavir with grazoprevir increased grazoprevir exposure; the geometric mean ratio (GMR) for grazoprevir plus ritonavir versus grazoprevir alone area under the concentration-time curve from 0 to 24 h (AUC) was 1.91 (90% confidence interval [CI]; 1.31 to 2.79). Grazoprevir exposure was markedly increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for grazoprevir AUC of 10.58 (90% CI, 7.78 to 14.39), 12.86 (90% CI, 10.25 to 16.13), and 7.50 (90% CI, 5.92 to 9.51), respectively. Elbasvir exposure was increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for elbasvir AUC of 4.76 (90% CI, 4.07 to 5.56), 3.71 (90% CI, 3.05 to 4.53), and 1.66 (90% CI, 1.35 to 2.05), respectively. Grazoprevir and elbasvir had little effect on atazanavir, lopinavir, and darunavir pharmacokinetics. Coadministration of elbasvir-grazoprevir with atazanavir-ritonavir, lopinavir-ritonavir, or darunavir-ritonavir is contraindicated, owing to an increase in grazoprevir exposure. Therefore, HIV treatment regimens without HIV protease inhibitors should be considered for HCV/HIV-coinfected individuals who are being treated with elbasvir-grazoprevir.
HCV 非结构蛋白 5A（NS5A）抑制剂 elbasvir 与 NS3/4A 蛋白酶抑制剂 grazoprevir 的联合用药是一种强效的每日一次治疗方案，适用于人类免疫缺陷病毒（HIV）合并感染的慢性 HCV 感染患者。我们在三项 I 期试验中研究了 elbasvir 和 grazoprevir 与利托那韦和利托那韦增强型 HIV 蛋白酶抑制剂的药代动力学相互作用。药物相互作用试验在健康参与者中进行，以评估利托那韦对 grazoprevir（=10）的药代动力学的影响，以及当与利托那韦增强型阿扎那韦、洛匹那韦或达芦那韦联合给药时，elbasvir（=30）或 grazoprevir（=39）的潜在双向药代动力学相互作用。与 grazoprevir 联合使用利托那韦增加了 grazoprevir 的暴露量；grazoprevir 加利托那韦与 grazoprevir 单药相比的 0 至 24 小时浓度-时间曲线下面积的几何均数比值（GMR）为 1.91（90%置信区间[CI]；1.31 至 2.79）。当与阿扎那韦-利托那韦、洛匹那韦-利托那韦和达芦那韦-利托那韦联合使用时，grazoprevir 的暴露量明显增加，grazoprevir AUC 的 GMR 分别为 10.58（90%CI，7.78 至 14.39）、12.86（90%CI，10.25 至 16.13）和 7.50（90%CI，5.92 至 9.51）。当与阿扎那韦-利托那韦、洛匹那韦-利托那韦和达芦那韦-利托那韦联合使用时，elbasvir 的暴露量增加，elbasvir AUC 的 GMR 分别为 4.76（90%CI，4.07 至 5.56）、3.71（90%CI，3.05 至 4.53）和 1.66（90%CI，1.35 至 2.05）。grazoprevir 和 elbasvir 对阿扎那韦、洛匹那韦和达芦那韦的药代动力学影响不大。由于 grazoprevir 暴露量增加，elbasvir-grazoprevir 与阿扎那韦-利托那韦、洛匹那韦-利托那韦或达芦那韦-利托那韦联合使用是禁忌的。因此，正在接受 elbasvir-grazoprevir 治疗的 HCV/HIV 合并感染患者，应考虑使用不含 HIV 蛋白酶抑制剂的 HIV 治疗方案。
