Background

Long-acting injectable cabotegravir is a novel integrase inhibitor currently in advanced clinical development for HIV prevention and treatment. We aimed to assess the terminal phase pharmacokinetics and safety of long-acting injectable cabotegravir in participants included in the HPTN 077 trial.

Methods

HPTN 077 was a multicentre, double-blind, randomised, placebo-controlled phase 2a trial done at eight sites in Brazil, Malawi, South Africa, and the USA. Participants (aged 18–65 years), who were HIV-uninfected and at low-risk for HIV, were randomly assigned (3:1) to long-acting injectable cabotegravir (800 mg given three times at 12 week intervals or 600 mg given five times, administered at one 4 week interval, and every 8 weeks thereafter) or placebo. Participants were followed up to 76 weeks after final injection. In a prespecified analysis of secondary and exploratory outcomes, we assessed the safety, measured by the proportion of participants with grade 2 or worse adverse events, and pharmacokinetics, measured by apparent terminal phase half-life (t_1/2app) and estimated time to lower limit of quantification (LLOQ) of long-acting injectable cabotegravir during the injection phase (defined as the time between first injection and 12 weeks or 8 weeks after the last injection in cohort 1 or cohort 2 respectively) and tail phase (defined as the time between final injection and 52–76 weeks post-final injection). Safety was analysed in all participants who received at least one injection. Pharmacokinetic analyses included all participants who had received at least one injection and had at least three cabotegravir measurements higher than the LLOQ after the final injection. Pharmacokinetic outcomes were estimated using non-compartmental methods. The trial is completed, and was registered with ClinicalTrials.gov, NCT02178800.

Findings

Between Feb 9, 2015, and May 27, 2016, 177 participants (134 participants in the cabotegravir group [74 participants in cohort 1; 60 participants in cohort 2] and 43 participants in the placebo group [25 participants in cohort 1; 18 participants in cohort 2) were enrolled and received at least one injection and thus were included in the safety analysis. The incidence of grade 2 or worse adverse events was significantly lower during the tail phase than the injection phase (p<0·0001). At 52–60 weeks after final injection, nine (23%) of 40 male participants had detectable cabotegravir concentrations and at week 76, four (13%) of 30 male participants had detectable cabotegravir concentrations compared with 52 (63%) of 82 female participants and 27 (42%) of 64 female participants at the same timepoints. The median time from the last injection to the time when cabotegravir concentration decreased below the LLOQ was 43·7 weeks (IQR 31·1–66·6; range 20·4–152·5) for male participants and 67·3 weeks (29·1–89·6; 17·7–225·5) for female participants (p=0·0003). t_1/2app was longer for female participants than male participants (geometric mean fold-change 1·33, 95% CI 1·06–1·68; p=0·014), and longer for participants with a high body-mass index (BMI) than those with a low BMI (1·31, 1·06–1·63; p=0·015).

Interpretation

The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials.

Funding

National Institute of Allergy and Infectious Diseases.

中文翻译：

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未感染 HIV 的成人中长效可注射 cabotegravir 的尾部安全性、耐受性和药代动力学：HPTN 077 试验的二次分析。

背景

长效可注射 cabotegravir 是一种新型整合酶抑制剂，目前处于 HIV 预防和治疗的高级临床开发阶段。我们旨在评估 HPTN 077 试验中包括的参与者中长效注射用卡博特韦的终末期药代动力学和安全性。

方法

HPTN 077 是一项多中心、双盲、随机、安慰剂对照的 2a 期试验，在巴西、马拉维、南非和美国的八个地点进行。未感染 HIV 且 HIV 风险较低的参与者（18-65 岁）被随机分配 (3:1) 至长效注射用卡博特拉韦组（800 毫克，间隔 12 周给药 3 次，或 600 毫克五次，每 4 周给药一次，此后每 8 周给药一次）或安慰剂。在最后一次注射后对参与者进行了长达 76 周的随访。在对次要和探索性结局的预设分析中，我们评估了安全性（通过发生 2 级或更严重不良事件的参与者比例衡量）和药代动力学（通过表观终末期半衰期 (t _1/2app) 和长效注射用卡博特韦在注射阶段（分别定义为第一次注射和最后一次注射后第 12 周或第 8 周之间的时间）和尾部的估计时间（LLOQ）阶段（定义为最后一次注射和最后一次注射后 52-76 周之间的时间）。对接受至少一次注射的所有参与者进行了安全性分析。药代动力学分析包括所有接受过至少一次注射并且在最后一次注射后至少 3 次 cabotegravir 测量值高于 LLOQ 的参与者。使用非房室方法估计药代动力学结果。该试验已完成，并已在 ClinicalTrials.gov 注册，NCT02178800。

发现

2015 年 2 月 9 日至 2016 年 5 月 27 日期间，177 名参与者（cabotegravir 组 134 名参与者 [队列 1 中的 74 名参与者；队列 2 中的 60 名参与者]和安慰剂组中的 43 名参与者 [队列 1 中的 25 名参与者；18 名参与者队列 2) 中的受试者被纳入并接受了至少一次注射，因此被包括在安全性分析中。尾部阶段 2 级或更严重不良事件的发生率显着低于注射阶段（p<0·0001）。在最后一次注射后 52-60 周，40 名男性参与者中有 9 名 (23%) 可检测到 cabotegravir 浓度，在第 76 周时，30 名男性参与者中有 4 名 (13%) 可检测到 cabotegravir 浓度，而 82 名女性中有 52 名 (63%)参与者和 64 名女性参与者中的 27 名 (42%) 在同一时间点。男性参与者从最后一次注射到卡博特韦浓度降至 LLOQ 以下的中位时间为 43·7 周（IQR 31·1-66·6；范围 20·4-152·5），67·3 周（ 29·1–89·6；17·7–225·5) 女性参与者 (p=0·0003)。吨女性参与者的_1/2app比男性参与者更长（几何平均倍数变化 1· _33，95 % CI 1·06–1·68；p=0·014），并且体重指数较高的参与者更长(BMI) 比那些低 BMI 的人 (1·31, 1·06–1·63; p=0·015)。

解释

与男性参与者相比，在女性参与者中观察到的 cabotegravir 长药代动力学尾巴的临床意义需要在未来的试验中得到解决。

资金

国家过敏和传染病研究所。