University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
AIDS. 2021 Jul 15;35(9):1413-1421. doi: 10.1097/QAD.0000000000002902.
To describe the pharmacokinetics, safety, and efficacy of etravirine (ETR) in HIV-infected children 1 to less than 6 years of age.
Phase I/II, open-label, multicenter, dose-finding study.
Antiretroviral therapy (ART)-experienced children in two age cohorts (I: 2 to <6 years; II: 1 to less than 2 years) received weight-based ETR, swallowed whole or dispersed in liquid, with optimized ART including a ritonavir-boosted protease inhibitor. Intensive pharmacokinetics occurred 7-18 days after starting ETR. Participants with ETR AUC12h less than 2350 ng h/ml had a dose increase and repeat pharmacokinetics.
Twenty-six children enrolled and 21 (15 in cohort I and 6 in cohort II) had evaluable intensive pharmacokinetics sampling at the final weight-based dose. On the final dose, the geometric mean ETR AUC12h was 3823 ng h/ml for cohort I and 3328 ng h/ml for cohort II. Seven children (33.3%) on the final dose, all taking ETR dispersed, had an AUC12 h less than 2350 ng h/ml and underwent a dose increase. ETR AUC12 h was 3.8-fold higher when ETR was swallowed whole vs. dispersed, P less than 0.0001. On the final dose, 75 and 33.3% in cohorts I and II, respectively, had HIV-1 RNA 400 copies/ml or less or at least 2 log reductions from baseline at week 48. Three children (11.5%) experienced a grade at least 3 adverse event related to ETR but only 1 discontinued.
ETR was well tolerated. Predefined pharmacokinetics targets were met but overall exposures were low vs. historical data in adults, particularly in young children taking dispersed tablets. A high rate of viral efficacy was observed among those aged 2 to more than 6 years but not in those less than 2 years.
描述依曲韦林（ETR）在 1 岁至 6 岁以下 HIV 感染儿童中的药代动力学、安全性和疗效。
I/II 期、开放性、多中心、剂量探索研究。
接受过抗逆转录病毒治疗（ART）的两个年龄组（I：2 至<6 岁；II：1 岁至<2 岁）的儿童，根据体重给予 ETR，整片吞服或分散在液体中，与优化的 ART 联合使用，包括利托那韦增效的蛋白酶抑制剂。在开始 ETR 后 7-18 天进行强化药代动力学采样。ETR AUC12h 低于 2350ng·h/ml 的参与者增加剂量并重复药代动力学采样。
26 名儿童入组，21 名（I 组 15 名，II 组 6 名）在最终体重剂量下有可评估的强化药代动力学采样。在最终剂量下，I 组和 II 组的 ETR AUC12h 的几何平均值分别为 3823ng·h/ml 和 3328ng·h/ml。7 名（33.3%）接受最终剂量、且均服用分散 ETR 的儿童的 AUC12h 低于 2350ng·h/ml，因此增加了剂量。与分散相比，整片吞服 ETR 时 AUC12h 增加了 3.8 倍，P 小于 0.0001。在最终剂量下，I 组和 II 组分别有 75%和 33.3%的儿童在第 48 周时 HIV-1 RNA 低于 400 拷贝/ml 或较基线至少下降 2 对数，在 2 岁以上的儿童中观察到病毒学疗效较好，但在 2 岁以下的儿童中未观察到。
ETR 具有良好的耐受性。虽然药代动力学目标得到了满足，但与成人的历史数据相比，总体暴露水平较低，尤其是在服用分散片剂的幼儿中。2 岁以上儿童的病毒学疗效较高，但 2 岁以下儿童的疗效不佳。
