Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Drugs for Neglected Diseases Initiative, Nairobi, Kenya.
J Antimicrob Chemother. 2023 Nov 6;78(11):2702-2714. doi: 10.1093/jac/dkad286.
To improve visceral leishmaniasis (VL) treatment in Eastern Africa, 14- and 28-day combination regimens of paromomycin plus allometrically dosed miltefosine were evaluated. As the majority of patients affected by VL are children, adequate paediatric exposure to miltefosine and paromomycin is key to ensuring good treatment response.
Pharmacokinetic data were collected in a multicentre randomized controlled trial in VL patients from Kenya, Sudan, Ethiopia and Uganda. Patients received paromomycin (20 mg/kg/day for 14 days) plus miltefosine (allometric dose for 14 or 28 days). Population pharmacokinetic models were developed. Adequacy of exposure and target attainment of paromomycin and miltefosine were evaluated in children and adults.
Data from 265 patients (59% ≤12 years) were available for this pharmacokinetic analysis. Paromomycin exposure was lower in paediatric patients compared with adults [median (IQR) end-of-treatment AUC0-24h 187 (162-203) and 242 (217-328) µg·h/mL, respectively], but were both within the IQR of end-of-treatment exposure in Kenyan and Sudanese adult patients from a previous study. Cumulative miltefosine end-of-treatment exposure in paediatric patients and adults [AUCD0-28 517 (464-552) and 524 (456-567) µg·day/mL, respectively] and target attainment [time above the in vitro susceptibility value EC90 27 (25-28) and 30 (28-32) days, respectively] were comparable to previously observed values in adults.
Paromomycin and miltefosine exposure in this new combination regimen corresponded to the desirable levels of exposure, supporting the implementation of the shortened 14 day combination regimen. Moreover, the lack of a clear exposure-response and exposure-toxicity relationship indicated adequate exposure within the therapeutic range in the studied population, including paediatric patients.
为改善东非地区内脏利什曼病（VL）的治疗效果，评估了巴龙霉素联合米替福新 14 天和 28 天组合疗法。由于大多数 VL 患者为儿童，因此确保米替福新和巴龙霉素在儿童中的充分暴露对于获得良好的治疗反应至关重要。
在肯尼亚、苏丹、埃塞俄比亚和乌干达进行的一项多中心随机对照试验中收集了药代动力学数据。患者接受巴龙霉素（14 天，每天 20mg/kg）联合米替福新（14 天或 28 天的体表面积剂量）治疗。建立群体药代动力学模型。评估儿童和成人中巴龙霉素和米替福新的暴露程度和目标达成情况。
共有 265 例患者（59%≤12 岁）纳入此项药代动力学分析。与成人相比，儿科患者的巴龙霉素暴露量较低[治疗结束时的 AUC0-24h 中位数（IQR）分别为 187（162-203）和 242（217-328）µg·h/mL]，但均在之前肯尼亚和苏丹成人患者治疗结束时的 IQR 范围内。儿科患者和成人的米替福新累积治疗结束时的暴露量[AUCD0-28 中位数（IQR）分别为 517（464-552）和 524（456-567）µg·day/mL]和目标达成[高于体外药敏值 EC90 的时间中位数（IQR）分别为 27（25-28）和 30（28-32）天]与之前成人观察到的结果相当。
新组合方案中，巴龙霉素和米替福新的暴露量与理想的暴露水平相符，支持采用 14 天的短疗程组合方案。此外，缺乏明确的暴露-反应和暴露-毒性关系表明，在研究人群中，包括儿科患者在内，治疗范围内的暴露量是足够的。
