Population pharmacokinetics of benznidazole in adult patients with Chagas disease

Abstract

The aim of the present study was to build a population pharmacokinetic (popPK) model to characterize benznidazole (BNZ) pharmacokinetics in adults with chronic Chagas disease. This study was a prospective, open-label, single-center clinical trial approved by the local ethics committee. Patients received BNZ at 2.5 mg/kg of body weight/12 h (Abarax, Elea Laboratory, Argentina) for 60 days. Plasma BNZ samples were taken several times during the study and analyzed by high-performance liquid chromatography with UV-visible detection (HPLC-UV). The popPK analysis was done with NONMEMv.7.3. Demographic and biological data were tested as covariates. Intraindividual, interoccasion, and residual variabilities were modeled. Internal and external validations were completed to assess the robustness of the model. Later on, simulations were performed to generate BNZ concentration-time course profiles for different dosage regimens. A total of 358 plasma BNZ concentrations from 39 patients were included in the analysis. A one-compartment PK model characterized by clearance (CL/F) and the apparent volume of distribution (V/F), with first-order absorption (Ka) and elimination, adequately described the data (CL/F, 1.73 liters/h; V/F, 89.6 liters; and Ka, 1.15 h(-1)). No covariates were found to be significant for CL/F and V/F. Internal and external validations of the final model showed adequate results. Data from simulations revealed that a dose of 2.5 mg/kg/12 h might lead to overexposure in most patients. A lower dose (2.5 mg/kg/24 h) was able to achieve trough BNZ plasma concentrations within the accepted therapeutic range of 3 to 6 mg/liter. In summary, we developed a population PK model for BNZ in adults with chronic Chagas disease. Dosing simulations showed that a BNZ dose of 2.5 mg/kg/24 h will adequately keep BNZ trough plasma concentrations within the recommended target range for the majority of patients. (This study has been registered at EudraCT under number 2011-002900-34 and at ClinicalTrials.gov under number NCT01755403.).

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Figures

FIG 1

Goodness-of-fit plots for the final population PK model. (Top left) Plot of population predictions (PRED) versus observed BNZ concentrations (OBS); (top right) plot of individual population predictions (IPRED) versus OBS; (bottom left) individual weighted population residuals (IWRES) versus IPRED; (bottom right) conditional weighted residuals (CWRES) versus time. Dashed line, line of identity (upper panels) or target line (lower panels); thick line, line indicating the general data trend. Concentrations (OBS, PRED, and IPRED) are given in milligrams per liter, and times are given in hours.

FIG 2

Visual predictive check. Comparisons were performed between the 5th, 95th (dashed lines), and 50th (solid line) percentiles obtained from 1,000 simulations and the observed BNZ plasma concentrations (open circles) for adult Chagas disease patients.

FIG 3

Box plots of percentage error (PE) and absolute percentage error (APE) for the validation data set as measures of bias and precision, respectively. The ordinates show percentages. The white band in each error box marks the 50th percentile; the box boundaries are at the 25th and 75th percentiles, and the limits of the whiskers are at the 10th and 90th percentiles. Other horizontal lines are “outliers,” i.e., values outside the 10th to 90th percentile range. IPE, percentage error for the individual predictions; PPE, percentage error for the population predictions; IAPE, absolute percentage error for the individual predictions; PAPE, absolute percentage error for the population predictions. Dashed line indicates target line.

FIG 4

Median BNZ concentrations versus time at steady state (from 1,000 simulated profiles) for a dose regimen of 2.5 mg/kg/24 h and different total body weights: 43 kg (dashed line), 70 kg (solid line), and 100 kg (dotted line). Trypanosomicidal concentrations range from 3 to 6 mg/liter. The median trough concentration at 24 h for 43 kg (dashed line) was 3.78 mg/liter, that for 70 kg (solid line) was 4.27 mg/liter, and that for 100 kg (dotted line) was 4.64 mg/liter (P > 0.05).