Liezl Gibhard, Mathew Njoroge, Mwila Mulubwa, Nina Lawrence, Dennis Smith, James Duffy, Claire Le Manach, Christel Brunschwig, Dale Taylor, Renier van der Westhuyzen, Leslie J Street, Gregory S Basarab, Kelly Chibale
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Dose-fractionation studies of a Plasmodium phosphatidylinositol 4-kinase inhibitor in a humanized mouse model of malaria.
UCT594 is a 2-aminopyrazine carboxylic acid Plasmodium phosphatidylinositol 4-kinase inhibitor with potent asexual blood-stage activity, the potential for interrupting transmission, as well as liver-stage activities. Herein, we investigated pharmacokinetic/pharmacodynamic (PK/PD) relationships relative to blood-stage activity toward predicting the human dose. Dose-fractionation studies were conducted in the Plasmodium falciparum NSG mouse model to determine the PK/PD indices of UCT594, using the in vivo minimum parasiticidal concentration as a threshold. UCT594 demonstrated concentration-dependent killing in the P. falciparum-infected NSG mouse model. Using this data and the preclinical pharmacokinetic data led to a low predicted human dose of <50 mg. This makes UCT594 an attractive potential antimalarial drug.
期刊介绍：
Antimicrobial Agents and Chemotherapy (AAC) features interdisciplinary studies that build our understanding of the underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy.
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