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Benznidazole, the first line therapy, has severe limitations such as poor tolerability and variable efficacy in the chronic stage of infection. To optimize dosing regimens, a better understanding of the pharmacokinetic\/pharmacodynamic (PK\/PD) relationship for benznidazole is crucial. This study aimed to characterize the population pharmacokinetic properties of benznidazole in mice and investigate the relationship between exposure and antitrypanosomal activity in <jats:italic>T. cruzi<\/jats:italic> infected mice.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methodology\/principal findings<\/jats:title>\n<jats:p>Antitrypanosomal activity was assessed in 118 BALB\/c mice with chronic-stage <jats:italic>T. cruzi<\/jats:italic> infection, utilizing highly sensitive in vivo bioluminescence imaging (BLI). Benznidazole was administered at doses ranging from 10 to 100\u2009mg\/kg for 5\u201320 days. The pharmacokinetic properties of benznidazole were evaluated in 52 uninfected BALB\/c mice using nonlinear mixed-effects modeling. The relationship between simulated benznidazole exposure and sterile parasitological cure in the BLI experiments was evaluated by logistic regression and partial least squares \u2013 discriminant analysis.<\/jats:p>\n<jats:p>Benznidazole pharmacokinetics in mice were well described by a one-compartment disposition model with first-order absorption, with higher doses associated with slower absorption. Univariate logistic regression revealed a significant correlation between drug exposure and the probability of parasitological cure. Total plasma exposure, time above IC<jats:sub>90<\/jats:sub> and peak plasma concentration were all strongly associated with efficacy, provided that benznidazole was administered for at least 5 days.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions\/significance<\/jats:title>\n<jats:p>This is the first study to successfully quantify the dose-response relationship for benznidazole in <jats:italic>T. cruzi<\/jats:italic>-infected mice using preclinical BLI data. Our results underscore the complexity of distinguishing PK\/PD drivers of efficacy due to high collinearity between PK\/PD index parameters, and we propose dose-fractionation studies for future research. Studying the PK\/PD relationship using the BLI model provides valuable insights, aiding hypothesis generation through endpoint assessment of parasite infection.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0012968","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T17:23:41Z","timestamp":1747157021000},"page":"e0012968","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pharmacokinetic-pharmacodynamic modeling of benznidazole and its antitrypanosomal activity in a murine model of chronic Chagas disease"],"prefix":"10.1371","volume":"19","author":[{"given":"Frauke","family":"Assmus","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayorinde","family":"Adehin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard 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