儿童患者中静脉注射 10-1074 和 VRC01LS 的安全性和药代动力学。
Safety and Pharmacokinetics of Intravenous 10-1074 and VRC01LS in Young Children.
机构信息
Department of Pediatrics, University of California, San Diego, La Jolla, CA.
Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.
出版信息
J Acquir Immune Defic Syndr. 2022 Oct 1;91(2):182-188. doi: 10.1097/QAI.0000000000003033.
BACKGROUND
Broadly neutralizing monoclonal antibodies (bNAbs) suppress HIV-1 RNA and may deplete residual viral reservoirs. We evaluated the safety and pharmacokinetics (PK) of dual intravenous VRC01LS and 10-1074 in very early-treated children with HIV-1 on suppressive antiretroviral treatment (ART).
SETTING
Botswana.
METHODS
Children with HIV-1 (median age 3.1 years) on ART from <7 days old were enrolled. In phase A, 6 children received 10-1074 (30 mg/kg at day 0, 28, and 56) and 6 children received VRC01LS (30 mg/kg at day 0, 10 mg/kg at days 28 and 56) by intravenous infusion. In phase B, 6 children received the 2 bNAbs combined (with higher VRC01LS maintenance dose, 15 mg/kg) every 4 weeks for 32 weeks with PK evaluations over 8 weeks. Population PK models were developed to predict steady-state concentrations.
RESULTS
BNAb infusions were well tolerated. There were no infusion reactions nor any bNAb-related grade 3 or 4 events. The median (range) first dose Cmax and trough (day 28) combined from both phases were 1405 (876-1999) μg/mL and 133 (84-319) μg/mL for 10-1074 and 776 (559-846) μg/mL and 230 (158-294) μg/mL for VRC01LS. No large differences in bNAb clearances were observed when given in combination. The estimated VRC01LS half-life was shorter than in adults. Predicted steady-state troughs [median (90% prediction interval)] were 261 (95-565) and 266 (191-366) μg/mL for 10-1074 and VRC01LS, respectively, when given in combination.
CONCLUSIONS
10-1074 and VRC01LS were safe and well-tolerated among children receiving ART. Troughs exceeded minimal targets with every 4-week administration of 10-1074 at 30 mg/kg and VRC01LS at 15 mg/kg.
背景
广泛中和单克隆抗体（bNAb）抑制 HIV-1 RNA 并可能耗尽残留的病毒库。我们评估了静脉注射 VRC01LS 和 10-1074 联合用药在接受抗逆转录病毒治疗（ART）的早期 HIV-1 儿童中的安全性和药代动力学（PK）。
地点
博茨瓦纳。
方法
接受 ART 的 HIV-1 儿童（中位年龄 3.1 岁）从<7 天开始入组。在 A 期，6 名儿童接受 10-1074（30 mg/kg，第 0、28 和 56 天），6 名儿童接受 VRC01LS（30 mg/kg，第 0、10 mg/kg，第 28 和 56 天）静脉输注。在 B 期，6 名儿童每 4 周接受 2 种 bNAb 联合治疗（VRC01LS 维持剂量较高，15 mg/kg），共 32 周，8 周内进行 PK 评估。建立群体 PK 模型以预测稳态浓度。
结果
bNAb 输注耐受良好。无输注反应，也无任何 bNAb 相关的 3 级或 4 级事件。来自两个阶段的第 1 剂 Cmax 和谷值（第 28 天）的中位数（范围）分别为 1405（876-1999）μg/mL 和 133（84-319）μg/mL 用于 10-1074 和 776（559-846）μg/mL 和 230（158-294）μg/mL 用于 VRC01LS。当联合使用时，bNAb 清除率没有明显差异。估计的 VRC01LS 半衰期短于成人。当联合使用时，预测的稳态谷值[中位数（95%预测区间）]分别为 261（95-565）和 266（191-366）μg/mL 用于 10-1074 和 VRC01LS。
结论
接受 ART 的儿童使用 10-1074 和 VRC01LS 安全且耐受良好。每 4 周给予 30 mg/kg 的 10-1074 和 15 mg/kg 的 VRC01LS，谷值超过最小目标。
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