Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 751 24, Sweden.
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 104 00, Thailand. Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, UK. Shoklo Malaria Research Unit (SMRU), Mae Sod 631 10, Thailand.
Sci Transl Med. 2014 Oct 29;6(260):260ra147. doi: 10.1126/scitranslmed.3005311.
A randomized, placebo-controlled trial conducted on the northwest border of Thailand compared malaria chemoprevention with monthly or bimonthly standard 3-day treatment regimens of dihydroartemisinin-piperaquine. Healthy adult male subjects (N = 1000) were followed weekly during 9 months of treatment. Using nonlinear mixed-effects modeling, the concentration-effect relationship for the malaria-preventive effect of piperaquine was best characterized with a sigmoidal Emax relationship, where plasma concentrations of 6.7 ng/ml [relative standard error (RSE), 23%] and 20 ng/ml were found to reduce the hazard of acquiring a malaria infection by 50% [that is, median inhibitory concentration (IC50)] and 95% (IC95), respectively. Simulations of monthly dosing, based on the final model and published pharmacokinetic data, suggested that the incidence of malaria infections over 1 year could be reduced by 70% with a recently suggested dosing regimen compared to the current manufacturer's recommendations for small children (8 to 12 kg). This model provides a rational framework for piperaquine dose optimization in different patient groups.
一项在泰国西北部边境进行的随机、安慰剂对照试验比较了疟疾化学预防与每月或每两个月标准的 3 天青蒿琥酯-哌喹治疗方案。1000 名健康成年男性受试者在 9 个月的治疗期间每周接受随访。使用非线性混合效应模型，哌喹的疟疾预防效果的浓度-效应关系最好用 S 形 Emax 关系来描述，其中发现血浆浓度为 6.7ng/ml[相对标准误差（RSE），23%]和 20ng/ml 分别将获得疟疾感染的风险降低 50%（即半数抑制浓度[IC50]）和 95%（IC95）。基于最终模型和已发表的药代动力学数据对每月给药进行模拟，与目前制造商针对 8 至 12 公斤儿童的建议相比，最近提出的给药方案可将 1 年内疟疾感染的发生率降低 70%。该模型为不同患者群体中的哌喹剂量优化提供了合理的框架。
