Pharmacokinetic-pharmacodynamic modeling of benznidazole and its antitrypanosomal activity in a murine model of chronic Chagas disease
Abstract
BACKGROUND: There is an urgent need for improved treatments for Chagas disease, a neglected tropical infection caused by the protozoan parasite Trypanosoma cruzi. 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 T. cruzi infected mice. METHODOLOGY/PRINCIPAL FINDINGS: Antitrypanosomal activity was assessed in 118 BALB/c mice with chronic-stage T. cruzi infection, utilizing highly sensitive in vivo bioluminescence imaging (BLI). Benznidazole was administered at doses ranging from 10 to 100 mg/kg for 5-20 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 - discriminant analysis. 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…
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