Merck & Co., Inc., Merck Research Labs, Kenilworth, New Jersey, USA.
PPD Development, Research, Las Vegas, Nevada, USA.
J Int AIDS Soc. 2021 Dec;24(12):e25858. doi: 10.1002/jia2.25858.
Hormonal contraceptives are among the most effective forms of reversible contraception, but many other compounds, including some antiretrovirals, have clinically meaningful drug-drug interactions (DDIs) with hormonal contraceptives. Islatravir is a novel human immunodeficiency virus nucleoside reverse transcriptase translocation inhibitor currently in clinical development for treatment and prevention of HIV infection. A phase 1 clinical trial was conducted to evaluate the DDI of islatravir and the combination of oral contraceptive levonorgestrel (LNG)/ethinyl estradiol (EE).
This was an open-label, two-period, fixed-sequence, DDI clinical trial in healthy, postmenopausal or bilaterally oophorectomized females aged 18 through 65 years in the United States between October 2016 and January 2017. A single dose of LNG 0.15 mg/EE 0.03 mg was given followed by a 7-day washout. Islatravir, 20 mg, was then dosed once weekly for 3 weeks; a single dose of LNG 0.15 mg/EE 0.03 mg was given concomitantly with the third dose of islatravir. Pharmacokinetic samples for plasma LNG and EE concentrations were collected pre-dose and up to 120 hours post-dose in each period. Safety and tolerability were assessed throughout the trial by clinical assessments, laboratory evaluations and examination of adverse events.
Fourteen participants were enrolled. The pharmacokinetics of LNG and EE were not meaningfully altered by co-administration with islatravir. For the comparison of (islatravir + LNG/EE)/(LNG/EE alone), the geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for LNG AUC and C were 1.13 (1.06, 1.20) and 0.965 (0.881, 1.06), respectively. For EE, the GMRs (90% CI) for AUC and C were 1.05 (0.981, 1.11) and 1.02 (0.971, 1.08), respectively. Co-administration of all three drugs was generally well tolerated.
The results of this trial support the use of LNG/EE contraceptives in combination with islatravir without dose adjustment.
激素避孕药是最有效的可逆避孕方法之一，但许多其他化合物，包括一些抗逆转录病毒药物，与激素避孕药存在有临床意义的药物相互作用（DDI）。伊斯拉特拉韦是一种新型人类免疫缺陷病毒核苷逆转录酶易位抑制剂，目前正在开发用于治疗和预防 HIV 感染。一项 1 期临床试验评估了伊斯拉特拉韦与口服避孕药左炔诺孕酮（LNG）/炔雌醇（EE）联合应用的药物相互作用。
这是一项在美国 18 至 65 岁绝经后或双侧卵巢切除的健康女性中进行的开放标签、两期、固定序列、DDI 临床试验，于 2016 年 10 月至 2017 年 1 月进行。给予 LNG 0.15mg/EE 0.03mg 单剂量，然后进行 7 天洗脱期。然后每周一次给予伊斯拉特拉韦 20mg，共 3 周；在给予伊斯拉特拉韦第 3 剂时同时给予 LNG 0.15mg/EE 0.03mg 单剂量。每个时期在给药前和给药后 120 小时内采集血浆 LNG 和 EE 浓度的药代动力学样本。通过临床评估、实验室评估和不良事件检查在整个试验过程中评估安全性和耐受性。
共纳入 14 名参与者。伊斯拉特拉韦联合用药并未显著改变 LNG 和 EE 的药代动力学。对于（伊斯拉特拉韦+LNG/EE/LNG/EE 单药）比较，LNG AUC 和 C 的几何均数比值（GMR）（90%置信区间[CI]）分别为 1.13（1.06，1.20）和 0.965（0.881，1.06）。对于 EE，AUC 和 C 的 GMR（90%CI）分别为 1.05（0.981，1.11）和 1.02（0.971，1.08）。联合使用这三种药物通常耐受性良好。
这项试验的结果支持在不调整剂量的情况下将 LNG/EE 避孕药与伊斯拉特拉韦联合使用。
