Background

Paediatric dolutegravir doses approved by stringent regulatory authorities (SRAs) for children weighing 20 kg to less than 40 kg until recently required 25 mg and 10 mg film-coated tablets. These tablets are not readily available in low-resource settings where the burden of HIV is highest. We did nested pharmacokinetic substudies in patients enrolled in the ODYSSEY-trial to evaluate simplified dosing in children with HIV.

Methods

We did pharmacokinetic and safety substudies within the open-label, multicentre, randomised ODYSSEY trial (NCT02259127) of children with HIV starting treatment in four research centres in Uganda and Zimbabwe. Eligible children were randomised to dolutegravir in ODYSSEY and weighed 20 kg to less than 40 kg. In children weighing 20 kg to less than 25 kg, we assessed dolutegravir's pharmacokinetics in children given once daily 25 mg film-coated tablets (approved by the SRAs at the time of the study) in part one of the study, and 50 mg film-coated tablets (adult dose) or 30 mg dispersible tablets in part two of the study. In children weighing 25 kg to less than 40 kg, we also assessed dolutegravir pharmacokinetics within-subject on film-coated tablet doses of 25 mg or 35 mg once daily, which were approved by the SRAs for the children's weight band; then switched to 50 mg film-coated tablets once daily. Steady-state 24 h dolutegravir plasma concentration-time pharmacokinetic profiling was done in all enrolled children at baseline and 1, 2, 3, 4, 6, and 24 h after observed dolutegravir intake. Target dolutegravir trough concentrations (C_trough) were based on reference adult pharmacokinetic data and safety was evaluated in all children in the corresponding weight bands who consented to pharmacokinetic studies and received the studied doses.

Findings

Between Sept 22, 2016, and May 31, 2018, we enrolled 62 black-African children aged from 6 years to younger than 18 years (84 pharmacokinetic-profiles). In children weighing 20 kg to less than 25 kg taking 25 mg film-coated tablets, the geometric mean (GM) C_trough (coefficient of variation) was 0·32 mg/L (94%), which was 61% lower than the GM C_trough of 0·83 mg/L (26%) in fasted adults on dolutegravir 50 mg once-daily; in children weighing 25 kg to less than 30 kg taking 25 mg film-coated tablets, the GM C_trough was 0·39 mg/L (48%), which was 54% lower than the GM C_trough in fasted adults; and in those 30 kg to less than 40 kg taking 35 mg film-coated tablets the GM C_trough was 0·46 mg/L (63%), which was 45% lower than the GM C_trough in fasted adults. On 50 mg film-coated tablets or 30 mg dispersible tablets, C_trough was close to the adult reference (with similar estimates on the two formulations in children in the 20 to <25 kg weight band), with total exposure (area under the concentration-time curve from 0 h to 24 h) in between reference values in adults dosed once and twice daily, where safety data are reassuring, although maximum concentrations were higher in children weighing 20 kg to less than 25 kg than in the twice-daily adult reference. Over a 24-week follow-up period in 47 children on 30 mg dispersible tablets or 50 mg film-coated tablets, none of the three reported adverse events (cryptococcal meningitis, asymptomatic anaemia, and asymptomatic neutropenia) were considered related to dolutegravir.

Interpretation

Adult dolutegravir 50 mg film-coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing 20 kg or more, with no safety signal, allowing simplified practical dosing and rapid access to dolutegravir. These results informed the WHO 2019 dolutegravir paediatric dosing guidelines and have led to US Food and Drug Administration approval of adult dosing down to 20 kg.

Funding

Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.

中文翻译：

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体重 20 公斤或以上的 HIV 儿童的简化多替拉韦给药：多中心随机 ODYSSEY 试验的药代动力学和安全性子研究。

背景

直到最近，由严格的监管机构 (SRA) 批准用于体重 20 公斤至低于 40 公斤的儿童的儿科多替拉韦剂量需要 25 毫克和 10 毫克的薄膜包衣片。在艾滋病毒负担最重的资源匮乏地区，这些药片并不容易获得。我们对参加 ODYSSEY 试验的患者进行了嵌套药代动力学子研究，以评估 HIV 儿童的简化给药。

方法

我们在乌干达和津巴布韦的四个研究中心开始治疗 HIV 儿童的开放标签、多中心、随机 ODYSSEY 试验 (NCT02259127) 中进行了药代动力学和安全性子研究。符合条件的儿童被随机分配到 ODYSSEY 中的 dolutegravir 组，体重在 20 公斤至 40 公斤以下。在体重 20 公斤至 25 公斤以下的儿童中，我们在研究的第一部分评估了每天一次给予 25 毫克薄膜包衣片（在研究时由 SRA 批准）和 50 毫克薄膜包衣片的儿童中多替拉韦的药代动力学。在研究的第二部分中，包衣片（成人剂量）或 30 mg 分散片。在体重 25 公斤至 40 公斤以下的儿童中，我们还评估了每天一次 25 毫克或 35 毫克的薄膜包衣片剂量的多替拉韦在受试者体内的药代动力学，这已获得 SRA 批准用于儿童 s 重量带；然后改用 50 毫克薄膜包衣片，每天一次。在基线和观察到多替拉韦摄入后 1、2、3、4、6 和 24 小时，对所有入选儿童进行了稳态 24 小时多替拉韦血浆浓度-时间药代动力学分析。目标多替拉韦谷浓度 (C_谷）基于参考成人药代动力学数据，并在所有同意进行药代动力学研究并接受研究剂量的相应体重范围内的儿童中评估安全性。

发现

2016 年 9 月 22 日至 2018 年 5 月 31 日期间，我们招募了 62 名年龄在 6 岁至 18 岁以下的非洲黑人儿童（84 份药代动力学特征）。体重 20 公斤至 25 公斤以下儿童服用 25 毫克薄膜衣片，其几何平均数 (GM) C_谷值（变异系数）为 0·32 毫克/升（94%），低于 61%每天服用一次 50 毫克多替拉韦，禁食成人的GM C_谷值为 0·83 毫克/升 (26%)；体重25公斤至30公斤以下的儿童服用25毫克薄膜衣片，转基因C_谷值为0·39毫克/升（48%），比禁食成人的转基因C_谷值低54% ；而在那些 30 公斤至 40 公斤以下服用 35 毫克薄膜衣片的 GM C_谷为 0·46 mg/L (63%)，比禁食成人的 GM C_谷低 45% 。在 50 mg 薄膜衣片或 30 mg 分散片上，C_槽接近成人参考值（对 20 至 <25 公斤体重范围内儿童的两种配方的估计值相似），总暴露量（0 小时至 24 小时的浓度-时间曲线下面积）介于参考值之间成人每天给药一次和两次，安全数据令人放心，尽管体重 20 公斤至 25 公斤以下的儿童的最大浓度高于每天两次的成人参考。在 47 名儿童服用 30 毫克分散片或 50 毫克薄膜衣片的 24 周随访期间，三项报告的不良事件（隐球菌性脑膜炎、无症状性贫血和无症状性中性粒细胞减少症）均被认为与多替拉韦有关。

解释

成人 dolutegravir 50 mg 薄膜包衣片每天给药一次，可在体重 20 kg 或以上的儿童中提供适当的药代动力学特征，没有安全信号，允许简化实际给药并快速获得 dolutegravir。这些结果通知了 WHO 2019 年 dolutegravir 儿科给药指南，并导致美国食品和药物管理局批准成人剂量降至 20 公斤。

资金

欧洲儿童艾滋病治疗网络基金会、ViiV 医疗保健、英国医学研究委员会。