Safety, Tolerability, Pharmacokinetics, and Acceptability of Oral and Long-Acting Cabotegravir in HIV-Negative Chinese Men.
Safety, Tolerability, Pharmacokinetics, and Acceptability of Oral and Long-Acting Cabotegravir in HIV-Negative Chinese Men.
复制标题
DOI：
10.1128/aac.02057-21
复制
发表时间：
2022-03-15
影响因子：
4.9
通讯作者：
Ford SL
中科院分区：
文献类型：
--
作者：
Han K;Wannamaker P;Lu H;Zhu B;Wang M;Paff M;Spreen WR;Ford SL
长效（LA）卡替拉韦在HIV-1暴露前预防治疗中表现出优于每日口服标准治疗的上级疗效。这项I期研究在47名HIV阴性、感染HIV-1风险较低的中国成年男性中评估了cabotegravir的安全性、耐受性、药代动力学和可接受性。受试者接受每日一次口服cabotegravir 30 mg，持续4周，在1周洗脱后，在第5、9、17、25和33周进行5次600 mg（3 mL）肌内cabotegravir LA注射。在第27天集中采集药代动力学血浆样本（n = 17），并在每次注射前稀疏采集，直至末次注射后56周（n = 47）。Cabotegravir LA注射剂可接受且耐受性良好。常见的不良事件包括注射部位疼痛、注射部位肿胀和上呼吸道感染。未发生药物相关严重不良事件或死亡。在每次注射前，平均cabotegravir浓度保持在1.33 μg/mL以上（8×体外蛋白质调整浓度，90%的病毒生长最大抑制[PA-IC 90]），在末次注射后超过32周保持在0.166 μg/mL以上（PA-IC 90）。几乎所有参与者的谷浓度均保持在PA-IC 90以上，并显示出极轻微的蓄积。进行非房室药代动力学分析。口服和LA给药后终末半衰期的几何平均值分别为1.89天和47天。估计卡替拉韦浓度在末次注射后48.7周内保持可定量。cabotegravir口服和LA给药后的稳态浓度-时间曲线下面积（AUC）、峰浓度、谷浓度、终末半衰期、达峰时间和表观清除率与历史研究中非亚洲男性的估计值相似。这些结果支持卡替拉韦LA在中国的进一步临床开发。(This研究已在ClinicalTrials.gov注册，注册号为NCT 03422172。）
Long-acting (LA) cabotegravir demonstrated superior efficacy versus daily oral standard-of-care for HIV-1 preexposure prophylaxis. This phase 1 study assessed safety, tolerability, pharmacokinetics, and acceptability of cabotegravir in 47 HIV-negative adult Chinese men at low risk of acquiring HIV-1. Participants received once-daily oral cabotegravir 30 mg for 4 weeks and, after a 1-week washout, five 600-mg (3-mL) intramuscular cabotegravir LA injections at weeks 5, 9, 17, 25, and 33. Pharmacokinetic plasma samples were intensively collected on day 27 (n = 17) and sparsely collected before each injection until 56 weeks after final injection (n = 47). Cabotegravir LA injections were acceptable and well tolerated. Common adverse events included injection site pain, injection site swelling, and upper respiratory tract infection. No drug-related serious adverse events or deaths occurred. Mean cabotegravir concentration remained above 1.33 μg/mL (8× in vitro protein-adjusted concentration for 90% of the maximum inhibition of viral growth [PA-IC90]) before each injection and above 0.166 μg/mL (PA-IC90) for >32 weeks after final injection. Trough concentrations remained above PA-IC90 in nearly all participants and showed minimal accumulation. Noncompartmental pharmacokinetic analysis was performed. Geometric mean of terminal half-life was 1.89 and 47 days after oral and LA dosing, respectively. Cabotegravir concentrations were estimated to remain quantifiable for 48.7 weeks after final injection. Steady-state area under the concentration-time curve (AUC), peak concentration, trough concentration, terminal half-life, time to peak concentration, and apparent clearance after cabotegravir oral and LA dosing were similar to those estimated in non-Asian men in historical studies. These results support further clinical development of cabotegravir LA in China. (This study has been registered at ClinicalTrials.gov under registration no. NCT03422172.)