Optimal kinetic exposures for classic and candidate antitrypanosomals.
Optimal kinetic exposures for classic and candidate antitrypanosomals.
复制标题
经典和候选抗锥虫药物的最佳动力学暴露。
DOI：
10.1093/jac/dkz160
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Shapiro,TheresaA
中科院分区：
文献类型：
--
作者：
Meyer,KirstenJ;Meyers,DavidJ;Shapiro,TheresaA
ObjectivesEfficacy is determined not only by size, but also by shape, of drug exposure. Here the critical importance of the temporal pattern of drug concentrations (pharmacokinetic profile) is examined for antitrypanosomalsin vitro.MethodsAnin vitrohollow-fibre cartridge system was used to study contrasting drug profiles with four clinically used agents and two experimental candidates against the deadly parasiteTrypanosoma brucei. Artificial kinetics were employed intentionally to favour either high peak concentration or sustained duration of drug.ResultsChanging the shape of drug exposure significantly impacted drug efficacy. Suramin, melarsoprol and pentamidine were concentration-driven and therefore more efficacious when applied as short-lived high peaks. In contrast, difluoromethylornithine (DFMO) was time-driven, and therefore maximally effective as a constant infusion. Kinetic preference was robust over a wide range of drug exposures. Promising clinical candidates SCYX-7158 (acoziborole) and fexinidazole (parent and sulfone) were concentration-driven, suggesting optimal clinical regimens would involve relatively high but intermittent dosing.ConclusionsAntitrypanosomals have an intrinsic pharmacokinetic driver for optimal efficacy, with important implications for clinical management and future candidate development.
