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Abstract：
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.
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.
摘要：
目的：改善东非内脏利什曼病（VL）的治疗，评估了巴龙霉素加等量剂量的米替福辛的14天和28天组合方案。由于受VL影响的大多数患者是儿童，充分的儿科暴露于米替福辛和巴龙霉素是确保良好治疗反应的关键。
方法：一项多中心随机对照试验收集了来自肯尼亚的VL患者的药代动力学数据，苏丹,埃塞俄比亚和乌干达。患者接受巴龙霉素（20mg/kg/天，持续14天）加米替福辛（异速剂量，持续14或28天）。建立了群体药代动力学模型。在儿童和成人中评估了巴龙霉素和米替福辛的暴露和目标达成的充分性。
结果：来自265名患者（59%≤12年）的数据可用于此药代动力学分析。与成人相比，儿科患者的巴龙霉素暴露量较低[中位数（IQR）治疗结束AUC0-24h187（162-203）和242（217-328）µg·h/mL，分别]，但在之前的研究中,肯尼亚和苏丹成年患者均在治疗结束暴露的IQR范围内.儿科患者和成人的累积米替福辛治疗结束暴露[AUCD0-28517（464-552）和524（456-567）µg·day/mL，分别]和目标达到[超过体外敏感性值EC9027（25-28）和30（28-32）天的时间，分别]与以前在成人中观察到的值相当。
结论：在这种新的组合方案中，巴龙霉素和米替福辛的暴露量符合理想的暴露水平，支持实施缩短的14天联合治疗方案。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的治疗范围内充分暴露，包括儿科患者。
方法：一项多中心随机对照试验收集了来自肯尼亚的VL患者的药代动力学数据，苏丹,埃塞俄比亚和乌干达。患者接受巴龙霉素（20mg/kg/天，持续14天）加米替福辛（异速剂量，持续14或28天）。建立了群体药代动力学模型。在儿童和成人中评估了巴龙霉素和米替福辛的暴露和目标达成的充分性。
结果：来自265名患者（59%≤12年）的数据可用于此药代动力学分析。与成人相比，儿科患者的巴龙霉素暴露量较低[中位数（IQR）治疗结束AUC0-24h187（162-203）和242（217-328）µg·h/mL，分别]，但在之前的研究中,肯尼亚和苏丹成年患者均在治疗结束暴露的IQR范围内.儿科患者和成人的累积米替福辛治疗结束暴露[AUCD0-28517（464-552）和524（456-567）µg·day/mL，分别]和目标达到[超过体外敏感性值EC9027（25-28）和30（28-32）天的时间，分别]与以前在成人中观察到的值相当。
结论：在这种新的组合方案中，巴龙霉素和米替福辛的暴露量符合理想的暴露水平，支持实施缩短的14天联合治疗方案。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的治疗范围内充分暴露，包括儿科患者。
