University of Western Australia, Medical School, Fremantle Hospital, Fremantle, Western Australia, Australia.
Curtin University, School of Pharmacy and Biomedical Sciences, Bentley, Western Australia, Australia.
Int J Antimicrob Agents. 2022 Jan;59(1):106482. doi: 10.1016/j.ijantimicag.2021.106482. Epub 2021 Nov 21.
The component drugs in the widely used antimalarial artemisinin combination therapy artemether-lumefantrine are lipophilic, with the possibility that recommended fixed doses in adults may lead to subtherapeutic concentrations and consequent treatment failure in overweight/obese individuals with malaria. The aim of this study was to investigate the pharmacokinetic properties of artemether, lumefantrine and their active metabolites dihydroartemisinin and desbutyl-lumefantrine in 16 normal-weight, overweight and obese healthy male volunteers [body mass index (BMI) categories ≤25 kg/m², >25-≤30 kg/m² and >30 kg/m², respectively; absolute range 19.3-37.2 kg/m²]. Participants received the conventional six doses of artemether-lumefantrine over 3 days, each dose comprising 80 mg artemether plus 480 mg lumefantrine administered with 6.7 g fat, and blood samples were collected at pre-specified time-points over 14 days. Plasma drug/metabolite concentrations were measured using liquid chromatography-mass spectrometry and included in multi-compartmental population pharmacokinetic models. There was a non-significant trend to a lower area under the plasma concentration-time curve with a higher body weight or BMI for dihydroartemisinin and especially artemether which was attenuated when normalized for mg/kg dose, but this relationship was not evident in the case of the more lipophilic lumefantrine and its metabolite desbutyl-lumefantrine. Simulated Day 7 plasma lumefantrine concentrations were >200 µg/L (the threshold at which Plasmodium falciparum recrudescences are minimized) in all participants. These results indicate that there is no need for artemether-lumefantrine dose modification in overweight and obese patients with malaria.
广泛使用的抗疟药物青蒿素联合疗法中的青蒿素和本芴醇这两种成分药物均具有亲脂性，如果按照推荐剂量固定给成人用药，可能导致超重/肥胖疟疾患者的治疗浓度不足，从而导致治疗失败。本研究旨在研究 16 名正常体重、超重和肥胖健康男性志愿者（体重指数[BMI]类别分别为≤25 kg/m²、>25-≤30 kg/m²和>30 kg/m²；绝对范围为 19.3-37.2 kg/m²）体内青蒿素、本芴醇及其活性代谢物双氢青蒿素和去乙基-本芴醇的药代动力学特性。参与者在 3 天内接受了常规的 6 次青蒿素-本芴醇剂量治疗，每次剂量包含 80 mg 青蒿素加 480 mg 本芴醇，与 6.7 g 脂肪一起服用，并在 14 天内的预定时间点采集血样。使用液相色谱-质谱法测量血浆药物/代谢物浓度，并将其纳入多室群体药代动力学模型。双氢青蒿素和青蒿素的药时曲线下面积与体重或 BMI 呈负相关趋势，但无统计学意义，当按 mg/kg 剂量归一化时，这种相关性减弱，但脂溶性更高的本芴醇及其代谢物去乙基-本芴醇则没有这种关系。模拟第 7 天的血浆本芴醇浓度在所有参与者中均>200 µg/L（这是最小化恶性疟原虫复发的阈值）。这些结果表明，在患有疟疾的超重和肥胖患者中，无需调整青蒿素-本芴醇的剂量。
