Population pharmacokinetics of artesunate and amodiaquine in African children
Population pharmacokinetics of artesunate and amodiaquine in African children
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DOI：
10.1186/1475-2875-8-200
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发表时间：
2009-08-20
期刊：
影响因子：
3
通讯作者：
Kiechel, Jean-Rene
中科院分区：
文献类型：
--
作者：
Stepniewska, Kasia;Taylor, Walter;Kiechel, Jean-Rene
背景：阿莫地喹（AQ）和青蒿琥酯（AS）在儿童中的药代动力学（PK）数据有限，儿童是疟疾的重要风险群体。本研究的目的是评估一种新开发和注册的固定剂量复方青蒿琥酯和阿莫地喹的PK特性。方法：在6个月至5岁的儿童中进行AS和AQ的前瞻性群体药代动力学研究。参与者被随机分配接受新的青蒿琥酯和阿莫地喹FDC或单独片剂中给予的相同药物。将儿童分为两组，每组70名（每个治疗组35名），分别评估AS和AQ的药代动力学特性。AS和AQ的主要药理活性代谢物双氢青蒿素（DHA）和去乙基阿莫地喹（DeAq）的群体药代动力学模型，以及总青蒿素抗疟疾活性（定义为DHA和青蒿琥酯的摩尔当量血浆浓度之和）的群体药代动力学模型使用非线性混合效应方法构建。通过估计血浆浓度-时间曲线下面积（AUC）之间的比值（和95%CI）比较产品之间的相对生物利用度。对于DeAq，松散制剂与固定联合制剂AUC的比值估计为1.043（95% CI：0.956 - 1.138）。对于DHA和总抗疟疾活性，AUC估计是相同的。青蒿琥酯被迅速吸收，水解为DHA，并消除。当患者急性患病时，首次给药后的血药浓度显著高于随后给药后的血药浓度，而随后给药后患者通常无发热且临床改善。阿莫地喹迅速转化为DeAq，然后消除，估计中位（范围）消除半衰期为9（7 - 12）天。两个治疗组的疗效相似，AS+AQ组的治愈率为0.946（95% CI：0.840-0.982），AS/AQ组为0.892（95% CI：0.787-0.947）。PCR证实复发的五名患者中有四名接受了< 10 mg/kg的AQ剂量。两种方案均耐受良好。没有儿童出现严重的治疗后腹泻（<1，000/mu L）。没有证据表明AQ剂量相关的肝毒性，但1例患者出现无症状的肝酶升高，在第28天消退。结论：联合配制的AS-AQ FDC的生物利用度与单独片剂的去乙基阿莫地喹、DHA和总抗疟活性相似。这些数据支持将这种新型AS-AQ FDC用于急性无并发症恶性疟疾儿童。
Background: Pharmacokinetic (PK) data on amodiaquine (AQ) and artesunate (AS) are limited in children, an important risk group for malaria. The aim of this study was to evaluate the PK properties of a newly developed and registered fixed dose combination (FDC) of artesunate and amodiaquine.Methods: A prospective population pharmacokinetic study of AS and AQ was conducted in children aged six months to five years. Participants were randomized to receive the new artesunate and amodiaquine FDC or the same drugs given in separate tablets. Children were divided into two groups of 70 (35 in each treatment arm) to evaluate the pharmacokinetic properties of AS and AQ, respectively. Population pharmacokinetic models for dihydroartemisinin (DHA) and desethylamodiaquine (DeAq), the principal pharmacologically active metabolites of AS and AQ, respectively, and total artemisinin anti-malarial activity, defined as the sum of the molar equivalent plasma concentrations of DHA and artesunate, were constructed using the non-linear mixed effects approach. Relative bioavailability between products was compared by estimating the ratios (and 95% CI) between the areas under the plasma concentration-time curves (AUC).Results: The two regimens had similar PK properties in young children with acute malaria. The ratio of loose formulation to fixed co-formulation AUCs, was estimated as 1.043 (95% CI: 0.956 to 1.138) for DeAq. For DHA and total anti-malarial activity AUCs were estimated to be the same. Artesunate was rapidly absorbed, hydrolysed to DHA, and eliminated. Plasma concentrations were significantly higher following the first dose, when patients were acutely ill, than after subsequent doses when patients were usually afebrile and clinically improved. Amodiaquine was converted rapidly to DeAq, which was then eliminated with an estimated median (range) elimination half-life of 9 (7 to 12) days. Efficacy was similar in the two treatments groups, with cure rates of 0.946 (95% CI: 0.840-0.982) in the AS+AQ group and 0.892 (95% CI: 0.787-0.947) in the AS/AQ group. Four out of five patients with PCR confirmed recrudescences received AQ doses < 10 mg/kg. Both regimens were well tolerated. No child developed severe, post treatment neutropaenia (< 1,000/mu L). There was no evidence of AQ dose related hepatotoxicity, but one patient developed an asymptomatic rise in liver enzymes that was resolving by Day-28.Conclusion: The bioavailability of the co-formulated AS-AQ FDC was similar to that of the separate tablets for desethylamodiaquine, DHA and the total anti-malarial activity. These data support the use this new AS-AQ FDC in children with acute uncomplicated falciparum malaria.