Table 1.
Summary of benznidazole dosing regimens investigated in T. cruzi chronically infected mice (bioluminescence imaging studies), along with simulated median plasma exposures and parasitological cure rates.
Table 2.
Parameter estimates of the final population pharmacokinetic model for benznidazole in uninfected BALB/c mice.
Fig 1.
Visual predictive check of the final population pharmacokinetic model for benznidazole (not prediction-corrected).
Open circles represent observed plasma benznidazole concentrations from 52 female BALB/c mice across all dose groups (10, 30, and 100 mg/kg), including 90 plasma concentrations above the lower limit of quantification (LLOQ). The solid red line represents the 50th percentile (median) and the dashed blue lines represent the 5th and 95th percentiles of the observed data. The shaded areas represent the 95% confidence intervals around the simulated 5th, 50th, and 95th percentiles. The horizontal dashed line represents the LLOQ (5 ng/mL = 0.005 µg/mL).
Fig 2.
Simulations of pharmacokinetic median profiles for benznidazole (BZN) according to different dosing regimens investigated in T. cruzi infected mice.
Simulations were based on the final population pharmacokinetic model and a 25 g mouse (median weight of mice in drug efficacy studies). Black solid lines represent the median of the simulated benznidazole plasma concentrations over time. The horizontal red line represents the IC90,plasma against the amastigote form of T. cruzi (Tulahuen strain). The dark blue and light blue horizontal lines represent two-fold higher and two-fold lower target concentrations, respectively.
Table 3.
Correlation matrix of plasma exposure variables for benznidazole, simulated for dosing regimens investigated in bioluminescence imaging studies in T. cruzi chronically infected mice. Correlation was assessed using Pearson correlation coefficients (https://cran.r-project.org/web/packages/corrtable/index.html). All coefficients were highly significant (p value < 0.001); CMAX, maximum plasma concentrations; AUC, area under the concentration-time curve for up to 12 hours and 24 hours after dosing (AUC12, AUC24), and cumulative AUC extrapolated to infinity (AUC∞); T>IC90, Time above IC90 in plasma.
Fig 3.
Relationship between benznidazole exposure and antitrypanosomal activity in T. cruzi infected mice.
Boxplots (upper panel) showing the distribution of (a) CMAX, (b) AUC12, (c) AUC 24, (d) AUC∞ and (e) T>IC90 for T. cruzi infected mice that were not cured (n=35) and cured (n=83). The midline indicates the median, the box corresponds to the interquartile range, and the whiskers extend up to 1.5 times the interquartile range. The lower panel shows corresponding predicted probabilities of antitrypanosomal activity, based on the logistic regression modeling. The solid blue line indicates the median and the shaded area the 95% CI around predicted probabilities.
Table 4.
Binary univariate logistic regression model diagnostics for the correlation between benznidazole exposure and the odds of parasitological cure in mice chronically infected with T. cruzi.
Fig 4.
Receiver Operating Characteristics (ROC) curves for logistic regression, evaluating the relationship between benznidazole plasma exposure and parasitological cure in mice.
The lines represent ROC curves for different exposure metrics: area under the concentration-time curve at 12 hours (AUC12) and 24 hours (AUC24) after dosing, cumulative AUC to infinity (AUC∞), maximum plasma concentration (CMAX), and time above the target concentration (T>IC90). The areas under the ROC curves are summarized in Table 4.
Table 5.
Predicted probabilities of parasitological cure in mice chronically infected with T.cruzi, and required benznidazole exposures in plasma.