Existing solid antiretroviral fixed-dose combination formulations are preferred over liquid formulations in children, but their suitability for neonates is unknown. We evaluated the pharmacokinetics and safety of paediatric abacavir–lamivudine fixed-dose dispersible tablets and ritonavir-boosted lopinavir granules in neonates. In this open-label, two-stage, single-arm, phase 1/2, pharmacokinetic and safety trial, generic abacavir– lamivudine (120:60 mg) double-scored dispersible tablets and lopinavir boosted with ritonavir (40:10 mg) granules were studied. Neonates exposed to HIV (≥37 weeks gestational age) of no more than 3 days of age with birthweights of 2000–4000 g were identified through routine care in a tertiary hospital in Cape Town, South Africa. In stage 1, the pharmacokinetics and safety of two single doses were assessed to select the multidose strategy for stage 2. Neonates received a single dose of abacavir–lamivudine (30:15 mg, a quarter of a tablet) and lopinavir boosted with ritonavir (40:10 mg - one sachet) orally between 3 days and 14 days of age, and a second dose of a quarter tablet of abacavir–lamivudine and lopinavir boosted with ritonavir (80:20 mg, two sachets) 10–14 days later in stage 1. The multidose strategy selected in stage 2 was a quarter of the abacavir–lamivudine (30:15 mg) fixed-dose dispersible tablet once per day and two sachets of the lopinavir boosted with ritonavir (80:20 mg) granules twice per day from birth to age 28 days. In both stages two intensive pharmacokinetic visits were done, one at less than 14 days of life (pharmacokinetics 1) and another 10–14 days later (pharmacokinetics 2). Safety visits were done 1–2 weeks after each pharmacokinetic visit. Primary objectives were to assess pharmacokinetics and safety of abacavir, lamivudine, and lopinavir. Pharmacokinetic endpoints were area under the concentration time curve (AUC), maximum concentration, and concentration at end of dosing interval in all participants with at least one evaluable pharmacokinetic visit. Safety endpoints included grade 3 or worse adverse events, and grade 3 or worse treatment-related adverse events, occurring between study drug initiation and end of study. This completed trial is registered with the Pan African Clinical Trials Registry (PACTR202007806554538). Between Aug 18, 2021, and Aug 18, 2022, 24 neonates were enrolled into the trial and received study drugs. Eight neonates completed stage 1, meeting interim pharmacokinetic and safety criteria. In stage 2, 16 neonates received study drugs. Geometric mean abacavir and lamivudine exposures (AUC) were higher at 6–14 days (51·7 mg × h/L for abacavir and 17·2 mg × h/L for lamivudine) than at 19–24 days of age (25·0 mg × h/L and 11·3 mg × h/L), whereas they were similar for lopinavir over this period (AUC 0–12 58·5 mg × h/L 46·4 mg × h/L). Abacavir geometric mean AUC0–24 crossed the upper reference range at pharmacokinetics 1, but rapidly decreased. Lamivudine and lopinavir AUC0–tau were within range. No grade 2 or worse adverse events were related to study drugs. One neonate had a grade 1 prolonged corrected QT interval using the Fridericia method that spontaneously resolved. Abacavir–lamivudine dispersible tablets and ritonavir-boosted lopinavir granules in neonates were safe and provided drug exposures similar to those in young infants. Although further safety data are needed, this regimen presents a new option for HIV prevention and treatment from birth. Accelerating neonatal pharmacokinetic studies of novel antiretroviral therapies is essential for neonates to also benefit from state-of-the-art treatments. Unitaid.

中文翻译：

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儿科阿巴卡韦拉米夫定固定剂量分散片和利托那韦增强洛匹那韦颗粒治疗暴露于 HIV 的新生儿（PETITE 研究）：一项开放标签、两阶段、单臂、1/2 期药代动力学和安全性试验

现有的固体抗逆转录病毒固定剂量组合制剂在儿童中优于液体制剂，但其对新生儿的适用性尚不清楚。我们评估了儿科阿巴卡韦拉米夫定固定剂量分散片和利托那韦强化洛匹那韦颗粒在新生儿中的药代动力学和安全性。在这项开放标签、两阶段、单臂、1/2 期药代动力学和安全性试验中，仿制药阿巴卡韦-拉米夫定（120:60 mg）双刻分散片和洛匹那韦加利托那韦（40:10 mg）增强研究了颗粒。通过南非开普敦一家三级医院的常规护理，对出生体重 2000-4000 g、出生不超过 3 天的 HIV 暴露新生儿（孕龄≥37 周）进行了鉴定。在第 1 阶段，评估了两个单剂量的药代动力学和安全性，以选择第 2 阶段的多剂量策略。新生儿接受单剂量阿巴卡韦-拉米夫定（30:15 mg，四分之一片）和洛匹那韦联合利托那韦加强治疗（ 40:10 mg - 一袋）在 3 天至 14 日龄期间口服，10-14 天后第二次服用四分之一片阿巴卡韦-拉米夫定和洛匹那韦，辅以利托那韦（80:20 mg，两袋）。第 1 阶段。第 2 阶段选择的多剂量策略是每天一次四分之一的阿巴卡韦-拉米夫定（30:15 mg）固定剂量分散片，以及两袋洛匹那韦，每次两次加利托那韦（80:20 mg）颗粒。从出生到年龄28天。在这两个阶段均进行了两次密集的药代动力学检查，一次是在出生后 14 天以内（药代动力学 1），另一次是在 10-14 天后（药代动力学 2）。每次药代动力学访视后 1-2 周进行安全性访视。主要目的是评估阿巴卡韦、拉米夫定和洛匹那韦的药代动力学和安全性。药代动力学终点是至少进行过一次可评估药代动力学访视的所有参与者的浓度时间曲线下面积 (AUC)、最大浓度和给药间隔结束时的浓度。安全性终点包括在研究药物开始和研究结束之间发生的 3 级或更严重的不良事件，以及 3 级或更严重的治疗相关不良事件。这项已完成的试验已在泛非临床试验注册中心注册 (PACTR202007806554538)。 2021年8月18日至2022年8月18日期间，24名新生儿参加了该试验并接受了研究药物。八名新生儿完成了第一阶段，符合临时药代动力学和安全标准。在第二阶段，16 名新生儿接受了研究药物。 6-14 日龄时阿巴卡韦和拉米夫定的几何平均暴露量 (AUC)（阿巴卡韦为 51·7 mg × h/L，拉米夫定为 17·2 mg × h/L）高于 19-24 日龄时（25·7 mg × h/L）。 0 mg × h/L 和 11·3 mg × h/L），而洛匹那韦在此期间的情况相似（AUC 0–12 58·5 mg × h/L 46·4 mg × h/L）。阿巴卡韦几何平均值 AUC0-24 在药代动力学 1 处跨越参考范围上限，但迅速下降。拉米夫定和洛匹那韦 AUC0-tau 均在范围内。没有与研究药物相关的 2 级或更严重的不良事件。使用弗里德里西亚方法，一名新生儿出现 1 级校正 QT 间期延长，并自行缓解。阿巴卡韦拉米夫定分散片和利托那韦强化洛匹那韦颗粒在新生儿中是安全的，并且药物暴露量与小婴儿相似。尽管还需要进一步的安全性数据，但该方案为从出生起预防和治疗艾滋病毒提供了新的选择。加速新型抗逆转录病毒疗法的新生儿药代动力学研究对于新生儿也受益于最先进的治疗至关重要。国际药品采购机制。