Khalilieh Sauzanne, Yee Ka Lai, Sanchez Rosa I, Triantafyllou Ilias, Fan Li, Maklad Noha, Jordan Heather, Martell Maureen, Iwamoto Marian
Merck & Co., Inc., Kenilworth, New Jersey, USA
Merck & Co., Inc., Kenilworth, New Jersey, USA.
Antimicrob Agents Chemother. 2017 Jan 24;61(2). doi: 10.1128/AAC.01364-16. Print 2017 Feb.
Doravirine is a novel, highly potent, nonnucleoside reverse transcriptase inhibitor that is administered once daily and that is in development for the treatment of HIV-1 infection. In vitro and clinical data suggest that doravirine is unlikely to cause significant drug-drug interactions via major drug-metabolizing enzymes or transporters. As a common HIV-1 infection comorbidity, hypercholesterolemia is often treated with statins, including the commonly prescribed atorvastatin. Atorvastatin is subject to drug-drug interactions with cytochrome P450 3A4 (CYP3A4) inhibitors. Increased exposure due to CYP3A4 inhibition may lead to serious adverse events (AEs), including rhabdomyolysis. Furthermore, atorvastatin is a substrate for breast cancer resistance protein (BCRP), of which doravirine may be a weak inhibitor; this may increase atorvastatin exposure. The potential of doravirine to affect atorvastatin pharmacokinetics was investigated in a two-period, fixed-sequence study in healthy individuals. In period 1, a single dose of atorvastatin at 20 mg was administered followed by a 72-h washout. In period 2, doravirine at 100 mg was administered once daily for 8 days, with a single dose of atorvastatin at 20 mg concomitantly being administered on day 5. Sixteen subjects were enrolled, and 14 completed the trial; 2 discontinued due to AEs unrelated to the treatment. The atorvastatin area under the curve from time zero to infinity was similar with and without doravirine (geometric mean ratio [GMR] for doravirine-atorvastatin/atorvastatin, 0.98; 90% confidence interval [CI], 0.90 to 1.06), while the maximum concentration decreased by 33% (GMR for doravirine-atorvastatin/atorvastatin, 0.67; 90% CI, 0.52 to 0.85). These changes were deemed not to be clinically meaningful. Both of the study drugs were generally well tolerated. Doravirine had no clinically relevant effect on atorvastatin pharmacokinetics in healthy subjects, providing support for the coadministration of doravirine and atorvastatin.
多韦拉韦是一种新型、高效的非核苷类逆转录酶抑制剂，每日给药一次，正在开发用于治疗HIV-1感染。体外和临床数据表明，多韦拉韦不太可能通过主要的药物代谢酶或转运体引起显著的药物相互作用。作为常见的HIV-1感染合并症，高胆固醇血症通常用他汀类药物治疗，包括常用的阿托伐他汀。阿托伐他汀会与细胞色素P450 3A4（CYP3A4）抑制剂发生药物相互作用。CYP3A4抑制导致的暴露增加可能会引发严重不良事件（AE），包括横纹肌溶解。此外，阿托伐他汀是乳腺癌耐药蛋白（BCRP）的底物，多韦拉韦可能是其弱抑制剂；这可能会增加阿托伐他汀的暴露量。在一项针对健康个体的两阶段固定序列研究中，研究了多韦拉韦对阿托伐他汀药代动力学的影响。在第1阶段，给予20 mg单剂量阿托伐他汀，随后进行72小时的洗脱期。在第2阶段，多韦拉韦100 mg每日给药一次，共8天，在第5天同时给予20 mg单剂量阿托伐他汀。招募了16名受试者，14名完成了试验；2名因与治疗无关的AE而停药。无论有无多韦拉韦，阿托伐他汀从零时间到无穷大的曲线下面积相似（多韦拉韦-阿托伐他汀/阿托伐他汀的几何平均比值[GMR]为0.98；90%置信区间[CI]为0.90至1.06），而最大浓度降低了33%（多韦拉韦-阿托伐他汀/阿托伐他汀的GMR为0.67；90%CI为0.52至0.85）。这些变化被认为无临床意义。两种研究药物总体耐受性良好。多韦拉韦对健康受试者的阿托伐他汀药代动力学无临床相关影响，为多韦拉韦与阿托伐他汀的联合给药提供了支持。
