Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Lancet HIV. 2023 Aug;10(8):e506-e517. doi: 10.1016/S2352-3018(23)00107-8.
Child-friendly fixed-dose combination (FDC) antiretroviral therapy (ART) options are limited. We evaluated the pharmacokinetics, safety, and tolerability of dispersible and immediate-release FDC abacavir, dolutegravir, and lamivudine taken once per day in children younger than 12 years with HIV.
IMPAACT 2019 was an international, phase 1-2, multisite, open-label, non-comparative dose-confirmation study of abacavir, dolutegravir, and lamivudine in children younger than 12 years. Participants were enrolled across five weight bands: those weighing 6 kg to less than 25 kg received abacavir (60 mg), dolutegravir (5 mg), and lamivudine (30 mg) dispersible tablets (three to six tablets depending on body weight), and those weighing 25 kg to less than 40 kg received abacavir (600 mg), dolutegravir (50 mg), and lamivudine (300 mg) in an immediate-release tablet. At entry, participants were ART naive or ART experienced and virologically suppressed on stable ART for 6 months or more. Dose confirmation was based on pharmacokinetic and safety criteria in the first five to seven participants in each weight band to week 4; all participants were followed up to week 48. We present the results for the primary objectives to assess pharmacokinetics, confirm dosing, and evaluate safety through 24 weeks across all weight bands. The trial is registered with ClinicalTrials.gov (NCT03760458).
57 children were enrolled and initiated study drug (26 [46%] female and 31 [54%] male; 37 [65%] Black, 18 [32%] Asian, and 1 [2%] had race reported as unknown). Within each weight band, 6 kg to less than 10 kg, 10 kg to less than 14 kg, 14 kg to less than 20 kg, 20 kg to less than 25 kg, and 25 kg or higher: the geometric mean dolutegravir area under the concentration time curve over the 24 h dosing interval (AUC) was 75·9 h·μg/mL (33·7%), 91·0 h·μg/mL (36·5%), 71·4 h·μg/mL (23·5%), 84·4 h·μg/mL (26·3%), and 71·8 h·μg/mL (13·9%); dolutegravir concentrations 24 h after dosage (C) were 0·91 μg/mL (67·6%), 1·22 μg/mL (77·5%), 0·79 μg/mL (44·2%), 1·35 μg/mL (95·5%), and 0·98 μg/mL (27·9%); abacavir AUC was 17·7 h·μg/mL (38·8%), 19·8 h·μg/mL (50·6%), 15·1 h·μg/mL (40·3%), 17·4 h·μg/mL (19·4%), and 25·7 h·μg/mL (14·6%); lamivudine AUC was 10·7 h·μg/mL (46·0%), 14·2 h·μg/mL (23·9%), 13·0 h·μg/mL (15·6%), 14·5 h·μg/mL (16·6%), and 21·7 h·μg/mL (26·2%), respectively. Pharmacokinetic targets and safety criteria were met within each weight band, and thus dosing of abacavir, dolutegravir, and lamivudine was confirmed at the originally selected doses. 54 (95%) of participants were treatment experienced and all who continued taking the study drug remained virologically suppressed (<200 copies per mL) through week 24. Virological suppression was achieved in two of three participants who were ART naive by week 24. There were no grade 3 or higher adverse events related to abacavir, dolutegravir, and lamivudine and no discontinuations because of toxicity to week 24. Both formulations were well tolerated.
Dosing of abacavir, dolutegravir, and lamivudine was confirmed in children weighing 6 kg to less than 40 kg, and both FDC formulations were safe, well tolerated, and efficacious through 24 weeks of treatment. These findings support global efforts to expand the availability of FDC abacavir, dolutegravir, and lamivudine to children with HIV.
National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, ViiV Healthcare, and GlaxoSmithKline.
儿童友好型固定剂量复方（FDC）抗逆转录病毒疗法（ART）选择有限。我们评估了 12 岁以下儿童单次服用可分散和速释阿巴卡韦、多替拉韦和拉米夫定 FDC 的药代动力学、安全性和耐受性。
IMPACT 2019 是一项国际性、1-2 期、多中心、开放性、非对照剂量确证研究，评估了 12 岁以下儿童中的阿巴卡韦、多替拉韦和拉米夫定。参与者根据五个体重组进行入组：体重 6kg 至<25kg 的参与者接受阿巴卡韦（60mg）、多替拉韦（5mg）和拉米夫定（30mg）可分散片（根据体重服用三至六片），体重 25kg 至<40kg 的参与者接受阿巴卡韦（600mg）、多替拉韦（50mg）和拉米夫定（300mg）速释片。入组时，参与者为初治或经治且在稳定的 ART 治疗下病毒载量抑制 6 个月或更长时间。根据前五个至七个每个体重组的参与者的药代动力学和安全性标准，在第 4 周确认剂量；所有参与者均随访至第 48 周。我们报告了所有体重组的主要目标结果，以评估药代动力学、确认剂量并在 24 周内评估安全性。该试验在 ClinicalTrials.gov 上注册（NCT03760458）。
57 名儿童入组并开始服用研究药物（26 名[46%]为女性，31 名[54%]为男性；37 名[65%]为黑人，18 名[32%]为亚洲人，1 名[2%]报告种族未知）。在每个体重组内，6kg 至<10kg、10kg 至<14kg、14kg 至<20kg、20kg 至<25kg 和 25kg 或更高：24 小时给药间隔时间内多替拉韦的 AUC0-24 几何平均值分别为 75.9h·μg/mL（33.7%）、91.0h·μg/mL（36.5%）、71.4h·μg/mL（23.5%）、84.4h·μg/mL（26.3%）和 71.8h·μg/mL（13.9%）；多替拉韦给药后 24 小时的 C 分别为 0.91μg/mL（67.6%）、1.22μg/mL（77.5%）、0.79μg/mL（44.2%）、1.35μg/mL（95.5%）和 0.98μg/mL（27.9%）；阿巴卡韦 AUC 分别为 17.7h·μg/mL（38.8%）、19.8h·μg/mL（50.6%）、15.1h·μg/mL（40.3%）、17.4h·μg/mL（19.4%）和 25.7h·μg/mL（14.6%）；拉米夫定 AUC 分别为 10.7h·μg/mL（46.0%）、14.2h·μg/mL（23.9%）、13.0h·μg/mL（15.6%）、14.5h·μg/mL（16.6%）和 21.7h·μg/mL（26.2%）。每个体重组内的药代动力学目标和安全性标准均得到满足，因此阿巴卡韦、多替拉韦和拉米夫定的剂量得到确认，剂量与最初选择的剂量相同。54 名（95%）参与者为经治，所有继续服用研究药物的参与者在第 24 周时病毒载量均持续抑制(<200 拷贝/mL)。24 周时，有 2/3 的初治参与者病毒载量得到抑制。在第 24 周时，有 2 名初治参与者达到了病毒学抑制，他们在入组前没有接受过抗逆转录病毒治疗。没有与阿巴卡韦、多替拉韦和拉米夫定相关的 3 级或更高级别的不良事件，也没有因毒性而在第 24 周时停药。两种制剂均具有良好的耐受性。
阿巴卡韦、多替拉韦和拉米夫定的剂量在体重 6kg 至<40kg 的儿童中得到确认，两种 FDC 制剂在 24 周的治疗期间具有安全性、耐受性和疗效。这些发现支持了扩大儿童艾滋病毒感染者使用阿巴卡韦、多替拉韦和拉米夫定 FDC 的全球努力。
美国国立过敏和传染病研究所、美国国家儿童健康和人类发展研究所、美国国家心理健康研究所、ViiV 医疗保健公司和葛兰素史克公司。
