Merck & Co., Inc., Rahway, New Jersey, USA.
Department of Pharmacology, Physiology & Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Antimicrob Agents Chemother. 2024 Sep 4;68(9):e0045824. doi: 10.1128/aac.00458-24. Epub 2024 Aug 6.
Antiretroviral therapy has substantially reduced morbidity, mortality, and disease transmission in people living with HIV. Islatravir is a nucleoside reverse transcriptase translocation inhibitor that inhibits HIV-1 replication by multiple mechanisms of action, and it is in development for the treatment of HIV-1 infection. In preclinical and clinical studies, islatravir had a long half-life (t) of 3.0 and 8.7 days (72 and 209 hours, respectively); therefore, islatravir is being investigated as a long-acting oral antiretroviral agent. A study was conducted to definitively elucidate the terminal t of islatravir and its active form islatravir-triphosphate (islatravir-TP). A single-site, open-label, non-randomized, single-dose phase 1 study was performed to evaluate the pharmacokinetics and safety of islatravir in plasma and the pharmacokinetics of islatravir-TP in peripheral blood mononuclear cells after administration of a single oral dose of islatravir 30 mg. Eligible participants were healthy adult males without HIV infection between the ages of 18 and 65 years. Fourteen participants were enrolled. The median time to maximum plasma islatravir concentration was 1 hour. Plasma islatravir concentrations decreased in a biphasic manner, with a t of 73 hours. The t (percentage geometric coefficient of variation) of islatravir-TP in peripheral blood mononuclear cells through 6 weeks (~1008 hours) after dosing was 8.1 days or 195 hours (25.6%). Islatravir was generally well tolerated with no drug-related adverse events observed. Islatravir-TP has a long intracellular t, supporting further clinical investigation of islatravir administered at an extended dosing interval.
抗逆转录病毒疗法大大降低了艾滋病毒感染者的发病率、死亡率和疾病传播率。伊拉司特韦是一种核苷逆转录酶易位抑制剂，通过多种作用机制抑制 HIV-1 复制，目前正在开发用于治疗 HIV-1 感染。在临床前和临床研究中，伊拉司特韦的半衰期（t）较长，分别为 3.0 天和 8.7 天（分别为 72 小时和 209 小时）；因此，伊拉司特韦被作为一种长效口服抗逆转录病毒药物进行研究。一项研究旨在明确伊拉司特韦及其活性形式伊拉司特韦三磷酸（伊拉司特韦-TP）的终末 t。进行了一项单部位、开放标签、非随机、单次剂量的 1 期研究，以评估单次口服伊拉司特韦 30 毫克后伊拉司特韦在血浆中的药代动力学和安全性，以及伊拉司特韦-TP 在周围血单核细胞中的药代动力学。符合条件的参与者为年龄在 18 至 65 岁之间、无 HIV 感染的健康成年男性。共纳入 14 名参与者。最大血浆伊拉司特韦浓度的中位时间为 1 小时。血浆伊拉司特韦浓度呈双相下降，t 为 73 小时。给药后 6 周（约 1008 小时）时，外周血单核细胞中伊拉司特韦-TP 的 t（几何系数变异百分比）为 8.1 天或 195 小时（25.6%）。伊拉司特韦总体耐受性良好，未观察到与药物相关的不良事件。伊拉司特韦-TP 具有较长的细胞内 t，支持进一步临床研究以延长伊拉司特韦的给药间隔。
