Background

Single-dose tafenoquine 300 mg is approved for Plasmodium vivax malaria relapse prevention in patients at least 16 years old. We aimed to determine appropriate oral tafenoquine paediatric dosing regimens, including a dispersible formulation, and evaluated tafenoquine efficacy and safety in children infected with P vivax.

Methods

This open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 study enrolled children (2–15 years) who weighed 5 kg or more, with glucose-6-phosphate dehydrogenase activity more than 70% of the local population median, and P vivax malaria infection, from three community health centres in Vietnam and one in Colombia. Patients received 3-day chloroquine plus oral single-dose tafenoquine as dispersible tablets (50 mg) or film-coated tablets (150 mg). Dosing groups were assigned by body weight, predicted to achieve similar median exposures as the approved 300 mg dose for adults: patients who weighed 5 kg or more to 10 kg received 50 mg, those who weighed more than 10 to 20 kg received 100 or 150 mg, those who weighed more than 20 to 35 kg received 200 mg, and patients who weighed more than 35 kg received 300 mg. Population pharmacokinetic analysis was done to develop a paediatric population pharmacokinetic model. The primary outcome was the tafenoquine area under the concentration–time curve extrapolated to infinity (AUC_[0–∞]) by patient body weight in the pharmacokinetic population (all patients who received tafenoquine with at least one valid pharmacokinetic sample) estimated from a paediatric population pharmacokinetic model. A key prespecified secondary outcome was 4-month recurrence-free efficacy. This trial is registered with ClinicalTrials.gov, NCT02563496.

Findings

Between Feb 6, 2017, and Feb 17, 2020, 60 patients were enrolled into the study: 14 (23%) received tafenoquine 100 mg, five (8%) 150 mg, 22 (36%) 200 mg, and 19 (32%) 300 mg. The paediatric population pharmacokinetic model predicted adequate tafenoquine exposure at all doses. The predicted median AUC_(0–∞) was 73·8 (90% prediction interval [PI] 46·9–117·0) μg × h/mL with the 50 mg dose for patients who weighed 5 kg or more to 10 kg, 87·5 (55·4–139·0) μg × h/mL with the 100 mg dose for body weight more than 10 to 20 kg, 110·7 (70·9–174·0) μg × h/mL with the 200 mg dose for body weight more than 20 to 35 kg, and 85·7 (50·6–151·0) μg × h/mL with the 300 mg dose for body weight more than 35 kg. 4-month recurrence-free efficacy was 94·7% (95% CI 84·6–98·3). Adverse events were consistent with previous studies, except for the seven (12%) of 60 patients who had post-dose vomiting or spitting with the 50 mg dispersed tablet. Following mitigation strategies, there were no additional occurrences of this adverse event. There were no deaths during the study.

Interpretation

For the prevention of P vivax relapse in children, single-dose tafenoquine, including a dispersible formulation, had exposure, safety, and efficacy consistent with observations in adolescents and adults, notwithstanding post-dose vomiting.

Funding

GlaxoSmithKline and Medicines for Malaria Venture.

Translations

For the Vietnamese and Spanish translations of the abstract see Supplementary Materials section.

中文翻译：

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间日疟原虫疟疾儿童的他非诺喹暴露评估、安全性和复发预防功效：开放标签、单臂、非比较、多中心、药代动力学桥接、2期试验

背景

单剂量 tafenoquine 300 mg 被批准用于至少 16 岁患者的间日疟原虫疟疾复发预防。我们旨在确定适当的口服他非诺喹儿科给药方案，包括可分散的制剂，并评估他非诺喹在感染间日疟原虫的儿童中的疗效和安全性。

方法

这项开放标签、单臂、非比较、多中心、药代动力学桥接的 2 期研究招募了体重 5 公斤或以上、葡萄糖-6-磷酸脱氢酶活性超过 70% 的儿童（2-15 岁）。当地人口中位数和P vivax疟疾感染，来自越南的三个社区卫生中心和哥伦比亚的一个社区卫生中心。患者接受为期 3 天的氯喹加口服单剂量他非诺喹作为分散片（50 毫克）或薄膜包衣片（150 毫克）。给药组按体重分配，预计达到与批准的成人 300 mg 剂量相似的中位暴露量：体重 5 公斤或以上至 10 公斤的患者接受 50 毫克，体重超过 10 至 20 公斤的患者接受 100 或 150 mg，体重超过 20 至 35 kg 的患者接受 200 mg，体重超过 35 kg 的患者接受 300 mg。进行群体药代动力学分析以建立儿科群体药代动力学模型。主要结局是外推至无穷大的浓度-时间曲线下的他非诺喹面积（AUC _[0-∞]) 通过从儿科群体药代动力学模型估计的药代动力学群体中的患者体重（所有接受他非诺喹且至少有一个有效药代动力学样本的患者）。一个关键的预设次要结果是 4 个月的无复发疗效。该试验已在 ClinicalTrials.gov 注册，NCT02563496。

发现

在 2017 年 2 月 6 日至 2020 年 2 月 17 日期间，60 名患者参加了研究：14 名（23%）接受了他非诺喹 100 毫克，5 名（8%）150 毫克，22 名（36%）200 毫克，19 名（32 %) 300 毫克。儿科人群药代动力学模型预测了所有剂量的他非喹的充分暴露。预测的中值 AUC _(0–∞)对于体重 5 kg 或以上至 10 kg 的患者，在 50 mg 剂量下为 73·8 (90% 预测区间 [PI] 46·9–117·0) μg × h/mL，87·5 (55·4– 139·0) μg × h/mL，100 mg 剂量，体重超过 10 到 20 kg，110·7 (70·9–174·0) μg × h/mL，200 mg 剂量，体重超过大于 20 至 35 kg，体重超过 35 kg 时 300 mg 剂量为 85·7 (50·6–151·0) μg × h/mL。4 个月无复发疗效为 94·7% (95% CI 84·6–98·3)。不良事件与之前的研究一致，除了 60 名患者中有 7 名（12%）在服用 50 mg 分散片剂后出现呕吐或吐痰。遵循缓解策略，没有额外发生这种不良事件。研究期间没有死亡。

解释

为了预防儿童间日疟原虫复发，单剂量他非诺喹（包括可分散制剂）的暴露量、安全性和有效性与青少年和成人的观察结果一致，尽管给药后呕吐。

资金

葛兰素史克和疟疾药物风险投资。

翻译

对于摘要的越南语和西班牙语翻译，请参阅补充材料部分。