一年一次来那卡巴韦的药代动力学和安全性，这一成果由吉利德科学公司Renu Singh团队经过不懈努力而取得。2025年3月11日出版的《柳叶刀》杂志发表了这一最新研究成果。

背景:长效抗逆转录病毒药物可以解决艾滋病毒暴露前预防（PrEP）的障碍，如耻辱感和依从性。在两项3期试验中，每年两次皮下lenacapavir对不同人群的PrEP是安全且高效的。为了进一步研究长效PrEP，本研究评估了两种每年一次肌注lenacapavir制剂的药代动力学和安全性。

方法:这项在18-55岁无HIV患者中进行的1期开放标签研究评估了两种无lenacapavir酸制剂的药代动力学、安全性和耐受性，这些制剂由腹肌肌内注射，单次剂量为5000mg（制剂1加5% w/w乙醇，制剂2加10% w/w乙醇）。在预定的时间点收集药代动力学样本，直至56周。用有效的液相色谱-串联质谱法测定Lenacapavir的血浆浓度，并用非区室分析进行总结。评估的药代动力学参数包括从第1天到365天（AUCdays 1 - 365）计算的一年一次给药间隔的浓度-时间曲线下面积、血药峰浓度、达到血药峰浓度的时间和谷浓度（Ctrough）。收集了每年两次皮下lenacapavir（目的1和目的2）的3期研究的血浆浓度数据，与每年一次肌肉注射lenacapavir制剂进行比较。评估安全性和耐受性，包括参与者报告的疼痛评分。

发现:

20名受试者接受lenacapavir制剂1,20名受试者接受lenacapavir制剂2。对于药代动力学参数的估计，样本量随着时间的推移而变化，由于与研究药物无关的原因早期停药，至少有13名参与者（配方1）和至少19名参与者（配方2）。肌注lenacapavir后浓度迅速升高，剂型1达到最大浓度的中位时间为84.1 d (IQR为56.1 ~ 11.2)，剂型2为69.9 d（55.3 ~ 105.5）。每年一次肌注lenacapavir的最高中位浓度（配方1为247.0 ng/mL [IQR 184·0 - 346·0]，配方2为336·0 ng/mL[235.3 - 474·3]）仍高于每年两次皮下lenacapavir的最高中位浓度（66.3 ng/mL[46.8 - 91.4]）。52周结束时，制剂1的中位通过量为57.0 ng/mL (IQR为49.9 ~ 72.4)，制剂2的中位通过量为65.6 ng/mL(41.8 ~ 87.1)，超过26周结束时每年两次的lenacapavir的中位通过量23.4 ng/mL（15.7 ~ 34.3）。配方1的中位AUCdays为1011.1 h*μg/mL (IQR为881.0 ~ 1490.2)，配方2的中位AUCdays为1274.0 h*μg/mL （IQR为1177.3 ~ 1704.8）。不良事件多为1级或2级。最常见的是注射部位疼痛（16名[80%]参与者服用制剂1,15名[75%]参与者服用制剂2），通常是轻微的，在1周内消退，并通过冰敷预处理大大减轻。

研究结果表明，在每年一次肌肉注射lenacapavir后，中位血浆浓度超过了每年两次皮下lenacapavir治疗PrEP至少56周的3期研究中与疗效相关的浓度。两种制剂均安全且耐受性良好。这些数据表明，每年一次的给药间隔在生物医学上预防艾滋病毒方面具有潜力。

附：英文原文

Title: Pharmacokinetics and safety of once-yearly lenacapavir: a phase 1, open-label study

Author: Vamshi Jogiraju, Pallavi Pawar, Jenna Yager, John Ling, Gong Shen, Anna Chiu, Emma Hughes, Ramesh Palaparthy, Christoph Carter, Renu Singh

Issue&Volume: 2025-03-11

Abstract: Background

Long-acting antiretrovirals can address barriers to HIV pre-exposure prophylaxis (PrEP), such as stigma and adherence. In two phase 3 trials, twice-yearly subcutaneous lenacapavir was safe and highly efficacious for PrEP in diverse populations. Furthering long-acting PrEP efforts, this study assessed the pharmacokinetics and safety of two once-yearly intramuscular lenacapavir formulations.

Methods

This phase 1, open-label study in participants aged 18–55 years without HIV evaluated the pharmacokinetics, safety, and tolerability of two lenacapavir free acid formulations administered by ventrogluteal intramuscular injection as a single 5000 mg dose (formulation 1 with 5% w/w ethanol, formulation 2 with 10% w/w ethanol). Pharmacokinetic samples were collected at prespecified timepoints up to 56 weeks. Lenacapavir plasma concentrations were measured with a validated liquid chromatography–tandem mass spectrometry method and summarised with non-compartmental analysis. Pharmacokinetic parameters evaluated included the area under the concentration–time curve for the once-yearly dosing interval calculated from days 1 to 365 (AUCdays 1–365), peak plasma concentration, time to reach peak plasma concentration, and trough concentration (Ctrough). Plasma concentration data from phase 3 studies of twice-yearly subcutaneous lenacapavir (PURPOSE 1 and PURPOSE 2) were pooled for comparison with once-yearly intramuscular lenacapavir formulations. Safety and tolerability, including participant-reported pain scores, were assessed.

Findings

20 participants received lenacapavir formulation 1 and 20 received lenacapavir formulation 2. For estimation of pharmacokinetic parameters, sample size varied over time with at least 13 participants (formulation 1) and at least 19 participants (formulation 2) due to early discontinuations for reasons unrelated to the study drug. Following administration of intramuscular lenacapavir, concentrations increased rapidly, and median time to maximum concentration was 84·1 days (IQR 56·1–112·0) for formulation 1 and 69·9 days (55·3–105·5) for formulation 2. The highest median concentration of once-yearly intramuscular lenacapavir (247·0 ng/mL [IQR 184·0–346·0] for formulation 1, 336·0 ng/mL [233·5–474·3] for formulation 2) remained above the highest median twice-yearly subcutaneous lenacapavir concentration (67·3 ng/mL [46·8–91·4]). Median Ctrough at the end of 52 weeks for formulation 1 was 57·0 ng/mL (IQR 49·9–72·4) and for formulation 2 was 65·6 ng/mL (41·8–87·1), exceeding the median twice-yearly subcutaneous lenacapavir Ctrough of 23·4 ng/mL (15·7–34·3) at the end of 26 weeks. Median AUCdays 1–365 for formulation 1 was 1011·1 h*μg/mL (IQR 881·0–1490·2) and for formulation 2 was 1274·0 h*μg/mL (1177·3–1704·8). Adverse events were mostly grade 1 or 2. The most common was injection-site pain (16 [80%] participants given formulation 1, 15 [75%] given formulation 2), which was generally mild, resolved within 1 week, and was substantially reduced by pretreatment with ice.

Interpretation

Following administration of once-yearly intramuscular lenacapavir, median plasma concentrations exceeded those associated with efficacy in phase 3 studies of twice-yearly subcutaneous lenacapavir for PrEP for at least 56 weeks. Both formulations were safe and well tolerated. These data show the potential for biomedical HIV prevention with a once-yearly dosing interval.

DOI: 10.1016/S0140-6736(25)00405-2

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00405-2/abstract