University of Western Australia, Medical School, Fremantle Hospital, Fremantle, Western Australia, Australia.
Universiti Malaysia Sarawak (UNIMAS) Malaria Research Centre, Kota Samarahan, Sarawak, Malaysia.
Br J Clin Pharmacol. 2022 Feb;88(2):691-701. doi: 10.1111/bcp.15001. Epub 2021 Aug 12.
The aim of this study was to assess the pharmacokinetic properties of artemether, lumefantrine and their active metabolites in Plasmodium knowlesi malaria.
Malaysian adults presenting with uncomplicated P. knowlesi infections received six doses of artemether (1.7 mg/kg) plus lumefantrine (10 mg/kg) over 3 days. Venous blood and dried blood spot (DBS) samples were taken at predetermined time-points over 28 days. Plasma and DBS artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine were measured using liquid chromatography-mass spectrometry. Multi-compartmental population pharmacokinetic models were developed using plasma with or without DBS drug concentrations.
Forty-one participants (mean age 45 years, 66% males) were recruited. Artemether-lumefantrine treatment was well tolerated and parasite clearance was prompt. Plasma and DBS lumefantrine concentrations were in close agreement and were used together in pharmacokinetic modelling, but only plasma concentrations of the other analytes were used because of poor correlation with DBS levels. The areas under the concentration-time curve (AUC ) for artemether, dihydroartemisinin and lumefantrine (medians 1626, 1881 and 625 098 μg.h/L, respectively) were similar to those reported in previous pharmacokinetic studies in adults and children. There was evidence of auto-induction of artemether metabolism (mean increase in clearance relative to bioavailability 25.2% for each subsequent dose). The lumefantrine terminal elimination half-life (median 9.5 days) was longer than reported in healthy volunteers and adults with falciparum malaria.
The disposition of artemether, dihydroartemisinin and lumefantrine in knowlesi malaria largely parallels that in other human malarias. DBS lumefantrine concentrations can be used in pharmacokinetic studies but DBS technology is currently unreliable for the other analytes.
本研究旨在评估青蒿琥酯、咯萘啶及其活性代谢物在伯氏疟原虫感染中的药代动力学特征。
马来西亚成年人患有未经治疗的伯氏疟原虫感染，接受 3 天内 6 剂青蒿琥酯（1.7mg/kg）加咯萘啶（10mg/kg）治疗。在 28 天内的预定时间点采集静脉血和干血斑（DBS）样本。使用液相色谱-质谱法测量血浆和 DBS 中的青蒿琥酯、二氢青蒿素、咯萘啶和去丁基-咯萘啶。使用包含或不包含 DBS 药物浓度的血浆建立多房室群体药代动力学模型。
共招募了 41 名参与者（平均年龄 45 岁，66%为男性）。青蒿琥酯-咯萘啶治疗耐受性良好，寄生虫清除迅速。血浆和 DBS 咯萘啶浓度密切一致，并在药代动力学建模中共同使用，但由于与 DBS 水平相关性差，仅使用其他分析物的血浆浓度。青蒿琥酯、二氢青蒿素和咯萘啶的浓度-时间曲线下面积（AUC）中位数分别为 1626、1881 和 625098μg.h/L，与以前在成人和儿童中进行的药代动力学研究报告的 AUC 相似。有证据表明青蒿琥酯代谢自动诱导（与生物利用度相比，每个后续剂量的清除率平均增加 25.2%）。咯萘啶的终末消除半衰期（中位数 9.5 天）长于健康志愿者和恶性疟原虫感染的成年人报告的半衰期。
青蒿琥酯、二氢青蒿素和咯萘啶在伯氏疟原虫感染中的处置在很大程度上与其他人类疟疾相似。DBS 咯萘啶浓度可用于药代动力学研究，但目前 DBS 技术对于其他分析物不可靠。
