Pharmacokinetics, Safety, and Efficacy of an Allometric Miltefosine Regimen for the Treatment of Visceral Leishmaniasis in Eastern African Children: An Open-label, Phase II Clinical Trial.
Pharmacokinetics, Safety, and Efficacy of an Allometric Miltefosine Regimen for the Treatment of Visceral Leishmaniasis in Eastern African Children: An Open-label, Phase II Clinical Trial.
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在东非儿童中治疗内脏利什曼病治疗的同量米尔特福赛方案的药代动力学，安全性和功效：一项开放标签的II期临床试验。
DOI：
10.1093/cid/ciy747
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发表时间：
2019-04-24
期刊：
影响因子：
--
通讯作者：
Alves F
中科院分区：
文献类型：
--
作者：
Mbui J;Olobo J;Omollo R;Solomos A;Kip AE;Kirigi G;Sagaki P;Kimutai R;Were L;Omollo T;Egondi TW;Wasunna M;Alvar J;Dorlo TPC;Alves F
东非儿童内脏利什曼病缺乏方便、安全和有效的治疗方法。米替福辛是唯一的口服疗法，未能取得足够的疗效，特别是在儿童中，线性剂量(2.5 mg/kg/天，28天)导致59%的治愈率，全身暴露低于成人。我们对30名4-12岁的内脏利什曼病儿童进行了II期试验，以测试28天的米替福辛异速给药是否安全地实现了比线性剂量更高的全身暴露。米替福辛在治疗过程中积累。0-210天的血药浓度时间曲线下的中位数面积和血浆最大血药浓度值略高于先前报道的线性给药儿童，但不是按剂量比例。治疗开始时米替福辛暴露增加，第7天血浆中位数浓度较高(5.88vs.2.67μg/mL)。浓度-时间曲线变化较小，避免了线性剂量下观察到的低水平暴露。210天的治愈率为90%(95%可信区间，73-98%)，与先前在成人中描述的类似。有19个与治疗相关的不良事件(AEs)，但没有一个导致治疗中断。严重不良反应2例，均与治疗无关，均痊愈出院。与线性剂量相比，米替福辛异速生长剂量获得了更多和变化更小的暴露，尽管没有达到预期的暴露水平。新的剂量方案安全地增加了米替福辛对患有内脏利什曼病的东非儿童的疗效。在儿科患者中，米替福辛的进一步开发应采用异速生长剂量。NCT02431143。在患有内脏利什曼病的东非儿童中，米替福辛异速生长剂量28天显示出比线性米替福辛剂量更多且变量更少的暴露，具有更好的疗效和令人满意的安全性。
Convenient, safe, and effective treatments for visceral leishmaniasis in Eastern African children are lacking. Miltefosine, the only oral treatment, failed to achieve adequate efficacy, particularly in children, in whom linear dosing (2.5 mg/kg/day for 28 days) resulted in a 59% cure rate, with lower systemic exposure than in adults. We conducted a Phase II trial in 30 children with visceral leishmaniasis, aged 4–12 years, to test whether 28 days of allometric miltefosine dosing safely achieves a higher systemic exposure than linear dosing. Miltefosine accumulated during treatment. Median areas under the concentration time curve from days 0–210 and plasma maximum concentration values were slightly higher than those reported previously for children on linear dosing, but not dose-proportionally. Miltefosine exposure at the start of treatment was increased, with higher median plasma concentrations on day 7 (5.88 versus 2.67 μg/mL). Concentration-time curves were less variable, avoiding the low levels of exposure observed with linear dosing. The 210-day cure rate was 90% (95% confidence interval, 73–98%), similar to that previously described in adults. There were 19 treatment-related adverse events (AEs), but none caused treatment discontinuation. There were 2 serious AEs: both were unrelated to treatment and both patients were fully recovered. Allometric miltefosine dosing achieved increased and less-variable exposure than linear dosing, though not reaching the expected exposure levels. The new dosing regimen safely increased the efficacy of miltefosine for Eastern African children with visceral leishmaniasis. Further development of miltefosine should adopt allometric dosing in pediatric patients. NCT02431143. Allometric miltefosine dosing for 28 days in Eastern African children with visceral leishmaniasis demonstrated increased and less-variable exposure than linear miltefosine dosing, with improved efficacy and a satisfactory safety profile.
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影响因子：
3.7
作者：
Ostyn B;Hasker E;Dorlo TP;Rijal S;Sundar S;Dujardin JC;Boelaert M
通讯作者：
Boelaert M
影响因子：
3.8
作者：
Wasunna M;Njenga S;Balasegaram M;Alexander N;Omollo R;Edwards T;Dorlo TP;Musa B;Ali MH;Elamin MY;Kirigi G;Juma R;Kip AE;Schoone GJ;Hailu A;Olobo J;Ellis S;Kimutai R;Wells S;Khalil EA;Strub Wourgaft N;Alves F;Musa A
通讯作者：
Musa A
影响因子：
11.8
作者：
Bhattacharya, SK;Jha, TK;Berman, JD
通讯作者：
Berman, JD
影响因子：
158.5
作者：
Sundar, S;Jha, TK;Berman, J
通讯作者：
Berman, J
影响因子：
158.5
作者：
Jha, TK;Sundar, S;Berman, J
通讯作者：
Berman, J