加纳无并发症恶性疟原虫病患者体内阿莫地喹及其活性代谢物去乙基阿莫地喹的药代动力学特征。
Pharmacokinetic profile of amodiaquine and its active metabolite desethylamodiaquine in Ghanaian patients with uncomplicated falciparum malaria.
机构信息
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
UCT/MRC Collaborating Centre for Optimising Antimalarial Therapy (CCOAT), University of Cape Town, Cape Town, South Africa.
出版信息
Malar J. 2021 Jan 6;20(1):18. doi: 10.1186/s12936-020-03553-6.
BACKGROUND
Accurate measurement of anti-malarial drug concentrations in therapeutic efficacy studies is essential to distinguish between inadequate drug exposure and anti-malarial drug resistance, and to inform optimal anti-malarial dosing in key target population groups.
METHODS
A sensitive and selective LC-MS/MS method was developed and validated for the simultaneous determination of amodiaquine and its active metabolite, desethylamodiaquine, and used to describe their pharmacokinetic parameters in Ghanaian patients with uncomplicated falciparum malaria treated with the fixed-dose combination, artesunate-amodiaquine.
RESULTS
The day-28 genotype-adjusted adequate clinical and parasitological response rate in 308 patients studied was > 97% by both intention-to-treat and per-protocol analysis. After excluding 64 patients with quantifiable amodiaquine concentrations pre-treatment and 17 with too few quantifiable concentrations, the pharmacokinetic analysis included 227 patients (9 infants, 127 aged 1-4 years, 91 aged ≥ 5 years). Increased median day-3 amodiaquine concentrations were associated with a lower risk of treatment failure [HR 0.87 (95% CI 0.78-0.98), p = 0.021]. Amodiaquine exposure (median AUC) was significantly higher in infants (4201 ng h/mL) and children aged 1-5 years (1994 ng h/mL) compared to older children and adults (875 ng h/mL, p = 0.001), even though infants received a lower mg/kg amodiaquine dose (median 25.3 versus 33.8 mg/kg in older patients). Desethylamodiaquine AUC was not significantly associated with age. No significant safety concerns were identified.
CONCLUSIONS
Efficacy of artesunate-amodiaquine at currently recommended dosage regimens was high across all age groups. Reassuringly, amodiaquine and desethylamodiaquine exposure was not reduced in underweight-for-age young children or those with high parasitaemia, two of the most vulnerable target populations. A larger pharmacokinetic study with close monitoring of safety, including full blood counts and liver function tests, is needed to confirm the higher amodiaquine exposure in infants, understand any safety implications and assess whether dose optimization in this vulnerable, understudied population is needed.
背景
在疗效研究中准确测量抗疟药物浓度对于区分药物暴露不足和抗疟药物耐药至关重要，并为关键目标人群提供最佳抗疟药物剂量。
方法
建立并验证了一种灵敏且选择性的 LC-MS/MS 方法，用于同时测定阿莫地喹及其活性代谢物去乙基阿莫地喹，并用其描述加纳患有无并发症恶性疟的患者在使用固定剂量复方青蒿琥酯阿莫地喹治疗时的药代动力学参数。
结果
308 例患者按意向治疗和方案分析的第 28 天基因型调整后充足临床和寄生虫学应答率均>97%。排除 64 例治疗前可定量阿莫地喹浓度和 17 例可定量浓度过少的患者后，药代动力学分析纳入 227 例患者（9 例婴儿、127 例 1-4 岁、91 例≥5 岁）。第 3 天阿莫地喹浓度中位数升高与治疗失败风险降低相关[风险比 0.87（95%CI 0.78-0.98），p=0.021]。与年龄较大的儿童和成人（875ng h/mL）相比，婴儿（4201ng h/mL）和 1-5 岁儿童（1994ng h/mL）的阿莫地喹暴露（中位数 AUC）显著更高，尽管婴儿接受的阿莫地喹剂量较低（mg/kg，婴儿 25.3 比年龄较大患者 33.8，p=0.001）。去乙基阿莫地喹 AUC 与年龄无显著相关性。未发现明显的安全性问题。
结论
目前推荐的青蒿琥酯阿莫地喹剂量方案在所有年龄组中的疗效均较高。令人安心的是，在体重不足的幼儿或高寄生虫血症的儿童中，阿莫地喹和去乙基阿莫地喹的暴露并未减少，这两个是最脆弱的目标人群。需要进行更大规模的药代动力学研究，并密切监测安全性，包括全血细胞计数和肝功能检查，以确认婴儿的阿莫地喹暴露更高，了解任何安全性影响，并评估在这个脆弱、研究不足的人群中是否需要优化剂量。
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