Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Antimicrob Chemother. 2019 Aug 1;74(8):2303-2310. doi: 10.1093/jac/dkz160.
Efficacy 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 antitrypanosomals in vitro.
An in vitro hollow-fibre cartridge system was used to study contrasting drug profiles with four clinically used agents and two experimental candidates against the deadly parasite Trypanosoma brucei. Artificial kinetics were employed intentionally to favour either high peak concentration or sustained duration of drug.
Changing 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.
Antitrypanosomals have an intrinsic pharmacokinetic driver for optimal efficacy, with important implications for clinical management and future candidate development.
药物暴露的效果不仅取决于其大小，还取决于其形状。本研究旨在探讨体外抗锥虫药物的药物浓度（药代动力学特征）时间模式的重要性。
采用中空纤维筒式系统，用四种临床应用药物和两种实验候选药物对致命寄生虫布氏锥虫进行对比药物特征研究。人为改变动力学特征，有利于药物浓度峰值高或药物持续时间长。
改变药物暴露的形状显著影响药物疗效。苏拉明、美拉胂醇和喷他脒是浓度依赖性的，因此作为短暂的高浓度时更有效。相比之下，二氟甲基鸟氨酸（DFMO）是时间依赖性的，因此作为持续输注时效果最佳。在广泛的药物暴露范围内，动力学偏好是稳健的。有前途的临床候选药物 SCYX-7158（阿卡波洛尔）和非奈硝唑（母体和砜）是浓度依赖性的，这表明最佳的临床方案将涉及相对较高但间歇性的给药。
抗锥虫药物具有内在的药代动力学驱动因素，以达到最佳疗效，这对临床管理和未来候选药物的开发具有重要意义。
