Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
Medical Research Council Clinical Trials Unit at University College London, University College London, London, UK.
Lancet HIV. 2022 May;9(5):e341-e352. doi: 10.1016/S2352-3018(21)00292-7. Epub 2022 Feb 18.
Dolutegravir-based antiretroviral therapy is a preferred first-line treatment for adults and children living with HIV; however, very little pharmacokinetic data for dolutegravir use are available in young children. We therefore aimed to evaluate dolutegravir dosing and safety in children weighing 3 kg to less than 20 kg by assessing pharmacokinetic parameters and safety data in children taking dolutegravir within the ODYSSEY trial.
We did pharmacokinetic substudies nested within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial. We enrolled children from seven research centres in South Africa, Uganda, and Zimbabwe. Children weighing 3 kg to less than 14 kg received 5 mg dispersible tablets of dolutegravir according to WHO weight bands: 5 mg for children weighing 3 kg to less than 6 kg and younger than 6 months, 10 mg for children weighing 3 kg to less than 6 kg and aged 6 months or older, 15 mg for children weighing 6 kg to less than 10 kg, and 20 mg for children weighing 10 kg to less than 14 kg. Children weighing 14 kg to less than 20 kg received a 25 mg film-coated tablet once per day early in the trial or 25 mg dispersible tablets (five 5 mg tablets once per day) later in the trial. A minimum of eight children per weight band or dose was targeted for 24 h pharmacokinetic profiling at steady state. The primary pharmacokinetic parameter was the trough concentration 24 h after observed dolutegravir intake (C). Pharmacokinetic targets were based on adult dolutegravir C and the 90% effective concentration (EC; ie, 0·32 mg/L). Safety was evaluated in eligible children consenting to pharmacokinetic substudies.
Between May 25, 2017, and Aug 15, 2019, we enrolled 72 children aged between 3 months and 11 years. 71 children were included in the safety population and 55 (76%) of 72 children contributed 65 evaluable pharmacokinetic profiles. Geometric mean C in children on dispersible tablets in weight bands between 3 kg and less than 20 kg ranged between 0·53-0·87 mg/L, comparable to the adult geometric mean C of 0·83 mg/L. Variability was high with coefficient of variation percentages ranging between 50% and 150% compared with 26% in adults. C below EC was observed in four (31%) of 13 children weighing 6 kg to less than 10 kg taking 15 mg dispersible tablets, and four (21%) of 19 weighing 14 kg to less than 20 kg taking 25 mg film-coated tablets. The lowest geometric mean C of 0·44 mg/L was observed in children weighing 14 kg to less than 20 kg on 25 mg film-coated tablets. Exposures were 1·7-2·0 times higher on 25 mg dispersible tablets versus 25 mg film-coated tablets. 19 (27%) of 71 children had 29 reportable grade 3 or higher adverse events (13 serious adverse events, including two deaths), none of which were related to dolutegravir.
Weight-band dosing of paediatric dolutegravir dispersible tablets provides appropriate drug exposure in most children weighing 3 kg to less than 20 kg, with no safety signal. 25 mg film-coated tablets did not achieve pharmacokinetic parameters in children weighing 14 kg to less than 20 kg, which were comparable to adults, suggesting dosing with dispersible tablets is preferable or a higher film-coated tablet dose is required.
Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, and UK Medical Research Council.
基于多替拉韦的抗逆转录病毒疗法是成人和儿童艾滋病毒感染者的首选一线治疗方法；然而，关于儿童使用多替拉韦的药代动力学数据非常有限。因此，我们旨在通过评估 ODYSSEY 试验中儿童使用多替拉韦的药代动力学参数和安全性数据，评估体重为 3 公斤至 20 公斤以下的儿童使用多替拉韦的多替拉韦剂量和安全性。
我们在 ODYSSEY 试验的开放性、多中心、随机、非劣效性试验中进行了药代动力学亚研究。我们从南非、乌干达和津巴布韦的 7 个研究中心招募了儿童。体重为 3 公斤至 14 公斤的儿童根据世界卫生组织体重带接受 5 毫克分散片的多替拉韦：体重为 3 公斤至 6 公斤且年龄小于 6 个月的儿童服用 5 毫克，体重为 3 公斤至 6 公斤且年龄为 6 个月或以上的儿童服用 10 毫克，体重为 6 公斤至 10 公斤的儿童服用 15 毫克，体重为 10 公斤至 14 公斤的儿童服用 20 毫克。体重为 14 公斤至 20 公斤的儿童在试验早期服用 25 毫克薄膜包衣片，或在试验后期服用 25 毫克分散片（每天一次，每次 5 片 5 毫克）。每个体重带或剂量至少有 8 名儿童在稳态下进行 24 小时药代动力学分析。主要药代动力学参数为多替拉韦摄入后 24 小时的谷浓度（C）。药代动力学靶标基于成人多替拉韦 C 和 90%有效浓度（EC；即 0.32 毫克/升）。在同意进行药代动力学亚研究的合格儿童中评估安全性。
在 2017 年 5 月 25 日至 2019 年 8 月 15 日期间，我们招募了 72 名年龄在 3 个月至 11 岁之间的儿童。71 名儿童纳入安全性人群，72 名儿童中有 55 名（76%）提供了 65 份可评估的药代动力学概况。体重为 3 公斤至 20 公斤的儿童服用分散片的几何平均 C 范围为 0.53-0.87 毫克/升，与成人几何平均 C（0.83 毫克/升）相当。与成人 26%的变异系数相比，儿童的变异系数百分比为 50%至 150%，差异很大。体重为 6 公斤至 10 公斤且服用 15 毫克分散片的 13 名儿童中有 4 名（31%），体重为 14 公斤至 20 公斤且服用 25 毫克薄膜包衣片的 19 名儿童中有 4 名（21%）的 C 低于 EC。体重为 14 公斤至 20 公斤且服用 25 毫克薄膜包衣片的儿童的几何平均 C 最低，为 0.44 毫克/升。与 25 毫克薄膜包衣片相比，25 毫克分散片的暴露量高 1.7-2.0 倍。71 名儿童中有 19 名（27%）发生 29 例可报告的 3 级或更高级别的不良事件（13 例严重不良事件，包括 2 例死亡），均与多替拉韦无关。
多替拉韦儿科分散片的体重带剂量为体重为 3 公斤至 20 公斤的大多数儿童提供了适当的药物暴露，无安全性信号。体重为 14 公斤至 20 公斤的儿童服用 25 毫克薄膜包衣片未达到与成人相当的药代动力学参数，这表明分散片的剂量更优，或需要更高的薄膜包衣片剂量。
儿科欧洲艾滋病治疗网络基金会、ViiV 医疗保健公司和英国医学研究理事会。
