Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Malaria Research and Training Centre (MRTC), Faculty of Pharmacy, Bamako, Mali.
Merck Institute of Pharmacometrics (an affiliate of Merck KGaA), Lausanne, Switzerland.
Nat Commun. 2024 Sep 3;15(1):7659. doi: 10.1038/s41467-024-51994-3.
The selection and combination of dose regimens for antimalarials involve complex considerations including pharmacokinetic and pharmacodynamic interactions. In this study, we use immediate ex vivo P. falciparum field isolates to evaluate the effect of cabamiquine and pyronaridine as standalone treatments and in combination therapy. We feed the data into a pharmacometrics model to generate an interaction map and simulate meaningful clinical dose ratios. We demonstrate that the pharmacometrics model of parasite growth and killing provides a detailed description of parasite kinetics against cabamiquine-susceptible and resistant parasites. Pyronaridine monotherapy provides suboptimal killing rates at doses as high as 720 mg. In contrast, the combination of a single dose of 330 mg cabamiquine and 360 mg pyronaridine provides over 90% parasite killing in most of the simulated patients. The described methodology that combines a rapid, 3R-compliant in vitro method and modelling to set meaningful doses for new antimalarials could contribute to clinical drug development.
抗疟药物剂量方案的选择和组合涉及到复杂的考虑因素，包括药代动力学和药效动力学的相互作用。在这项研究中，我们使用即时的体外疟原虫现场分离株来评估卡巴喹和咯萘啶作为单一治疗和联合治疗的效果。我们将数据输入到药代动力学模型中，生成相互作用图，并模拟有意义的临床剂量比。我们证明了寄生虫生长和杀伤的药代动力学模型提供了对抗卡巴喹敏感和耐药寄生虫的寄生虫动力学的详细描述。咯萘啶单药治疗在高达 720mg 的剂量下提供的杀伤率不理想。相比之下，330mg 卡巴喹和 360mg 咯萘啶的单剂量组合在大多数模拟患者中提供了超过 90%的寄生虫杀伤。该方法结合了快速、符合 3R 原则的体外方法和建模，为新的抗疟药物设定有意义的剂量，可能有助于临床药物开发。
