McCrea Jacqueline B, Patel Munjal, Liu Yang, Vargo Ryan, Witter Rose, Litovsky Andrew, Stoch S Aubrey, Iwamoto Marian, Matthews Randolph P
Merck & Co., Inc., Rahway, NJ, USA.
J Clin Pharmacol. 2025 May;65(5):628-636. doi: 10.1002/jcph.6169. Epub 2024 Nov 26.
Islatravir, a deoxyadenosine analog that inhibits HIV-1 replication by multiple mechanisms of action, including reverse transcriptase translocation inhibition, is being developed for use in HIV-1 treatment. People living with HIV often have comorbidities, such as dyslipidemia or type 2 diabetes mellitus, necessitating long-term concomitant drug therapy. This nonrandomized, two-period, fixed-sequence, open-label, phase 1, drug-drug interaction study was conducted to evaluate the effects of islatravir coadministration on atorvastatin and metformin pharmacokinetics (PK) in healthy adults. In period 1, participants received a single dose of atorvastatin 20 mg and metformin 1000 mg. After a 5-day washout, participants received atorvastatin 20 mg and metformin 1000 mg coadministered with a single oral dose of islatravir 60 mg (period 2). In both periods, blood samples were collected up to 72 h post dose to characterize the plasma PK of atorvastatin and metformin. Safety was monitored throughout the study. Fourteen participants were enrolled and completed the study. Atorvastatin and metformin plasma PK were similar after administration of atorvastatin and metformin with or without islatravir. The geometric mean ratio and 90% confidence interval of the area under the concentration-time curve from time zero to infinity (AUC) for atorvastatin and metformin with or without a single oral dose of islatravir were 1.04 (1.00-1.10) and 0.87 (0.79-0.96), respectively. Coadministration of islatravir with atorvastatin and metformin was well tolerated. Overall, coadministration of atorvastatin and metformin with a single oral dose of islatravir did not have a clinically meaningful effect on the PK profiles of either drug.
依斯拉曲韦是一种脱氧腺苷类似物，通过多种作用机制抑制HIV-1复制，包括抑制逆转录酶易位，目前正被开发用于HIV-1治疗。感染HIV的人通常患有合并症，如血脂异常或2型糖尿病，需要长期联合药物治疗。这项非随机、两阶段、固定序列、开放标签的1期药物相互作用研究旨在评估依斯拉曲韦联合给药对健康成年人阿托伐他汀和二甲双胍药代动力学（PK）的影响。在第1阶段，参与者接受单剂量20 mg阿托伐他汀和1000 mg二甲双胍。经过5天的洗脱期后，参与者接受20 mg阿托伐他汀、1000 mg二甲双胍与单剂量口服60 mg依斯拉曲韦联合给药（第2阶段）。在两个阶段，给药后最多72小时采集血样，以表征阿托伐他汀和二甲双胍的血浆PK。在整个研究过程中监测安全性。14名参与者入组并完成了研究。给予阿托伐他汀和二甲双胍，无论是否联合依斯拉曲韦，其血浆PK相似。阿托伐他汀和二甲双胍在联合或不联合单剂量口服依斯拉曲韦情况下，从零至无穷大的浓度-时间曲线下面积（AUC）的几何平均比值和90%置信区间分别为1.04（1.00-1.10）和0.87（0.79-0.96）。依斯拉曲韦与阿托伐他汀和二甲双胍联合给药耐受性良好。总体而言，阿托伐他汀和二甲双胍与单剂量口服依斯拉曲韦联合给药对两种药物的PK曲线均无临床意义上的影响。
