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
{"title":"Dose-fractionation studies of a <i>Plasmodium</i> phosphatidylinositol 4-kinase inhibitor in a humanized mouse model of malaria.","authors":"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","doi":"10.1128/aac.00842-24","DOIUrl":null,"url":null,"abstract":"<p><p>UCT594 is a 2-aminopyrazine carboxylic acid <i>Plasmodium</i> 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 <i>Plasmodium falciparum</i> NSG mouse model to determine the PK/PD indices of UCT594, using the <i>in vivo</i> minimum parasiticidal concentration as a threshold. UCT594 demonstrated concentration-dependent killing in the <i>P. falciparum</i>-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.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Antimicrobial Agents and Chemotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1128/aac.00842-24","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.