Frauke Assmus, Ayorinde Adehin, Richard M Hoglund, Amanda Fortes Francisco, Michael D Lewis, John M Kelly, Susan A Charman, Karen L White, David M Shackleford, Fanny Escudié, Eric Chatelain, Ivan Scandale, Joel Tarning
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Pharmacokinetic-pharmacodynamic modeling of benznidazole and its antitrypanosomal activity in a murine model of chronic Chagas disease.
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 correlation between drug exposure and the probability of parasitological cure. Total plasma exposure, time above IC90 and peak plasma concentration were all strongly associated with efficacy, provided that benznidazole was administered for at least 5 days.
Conclusions/significance: This is the first study to successfully quantify the dose-response relationship for benznidazole in T. cruzi-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.
期刊介绍:
PLOS Neglected Tropical Diseases publishes research devoted to the pathology, epidemiology, prevention, treatment and control of the neglected tropical diseases (NTDs), as well as relevant public policy.
The NTDs are defined as a group of poverty-promoting chronic infectious diseases, which primarily occur in rural areas and poor urban areas of low-income and middle-income countries. Their impact on child health and development, pregnancy, and worker productivity, as well as their stigmatizing features limit economic stability.
All aspects of these diseases are considered, including:
Pathogenesis
Clinical features
Pharmacology and treatment
Diagnosis
Epidemiology
Vector biology
Vaccinology and prevention
Demographic, ecological and social determinants
Public health and policy aspects (including cost-effectiveness analyses).