The healthcare business of Merck KGaA, Darmstadt, Germany.
iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.
Malar J. 2022 May 15;21(1):151. doi: 10.1186/s12936-022-04171-0.
Targeting the asymptomatic liver stage of Plasmodium infection through chemoprevention could become a key intervention to reduce malaria-associated incidence and mortality.
M5717, a Plasmodium elongation factor 2 inhibitor, was assessed in vitro and in vivo with readily accessible Plasmodium berghei parasites. In an animal refinement, reduction, replacement approach, the in vitro IC value was used to feed a Population Pharmacokinetics modelling and simulation approach to determine meaningful effective doses for a subsequent Plasmodium sporozoite-induced volunteer infection study.
Doses of 100 and 200 mg would provide exposures exceeding IC in 96 and 100% of the simulated population, respectively.
This approach has the potential to accelerate the search for new anti-malarials, to reduce the number of healthy volunteers needed in a clinical study and decrease and refine the animal use in the preclinical phase.
通过化学预防来针对疟原虫感染的无症状肝脏阶段，可能成为降低疟疾相关发病率和死亡率的关键干预措施。
M5717 是一种疟原虫延伸因子 2 抑制剂，在体外和体内使用易于获得的伯氏疟原虫寄生虫进行了评估。在动物优化、减少、替代方法中，体外 IC 值被用于群体药代动力学建模和模拟方法，以确定后续疟原虫子孢子诱导的志愿者感染研究的有意义的有效剂量。
100 和 200mg 的剂量将分别为模拟人群中 96%和 100%的个体提供超过 IC 的暴露。
这种方法有可能加速寻找新的抗疟药物，减少临床研究中所需的健康志愿者数量，并减少和优化临床前阶段的动物使用。
