title: 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.).
authors.affiliation: Pharmacy Service, Hospital Clinic Barcelona, Barcelona, Spain Institut de Investigació Biomèdica Agustí Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain CIBERES (CIBER de Enfermedades Respiratorias, 06/06/0028), Spain dsoy@clinic.ub.es.
authors.forename: D
authors.initials: D
authors.lastname: Soy
authors.affiliation: International Health Service, Hospital Clinic Barcelona, Barcelona, Spain ISGlobal, Barcelona Center for International Health Research (CRESIB), Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Aldasoro
authors.affiliation: CIBERES (CIBER de Enfermedades Respiratorias, 06/06/0028), Spain CELLEX Laboratory, University of Barcelona, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Guerrero
authors.affiliation: International Health Service, Hospital Clinic Barcelona, Barcelona, Spain ISGlobal, Barcelona Center for International Health Research (CRESIB), Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Posada
authors.affiliation: International Health Service, Hospital Clinic Barcelona, Barcelona, Spain ISGlobal, Barcelona Center for International Health Research (CRESIB), Barcelona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Serret
authors.affiliation: International Health Service, Hospital Clinic Barcelona, Barcelona, Spain ISGlobal, Barcelona Center for International Health Research (CRESIB), Barcelona, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Mejía
authors.affiliation: Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela.
authors.forename: J A
authors.initials: JA
authors.lastname: Urbina
authors.affiliation: International Health Service, Hospital Clinic Barcelona, Barcelona, Spain ISGlobal, Barcelona Center for International Health Research (CRESIB), Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Gascón
mesh_terms: D000328:Adult; D014355:Chagas Disease / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009593:Nitroimidazoles / Q000493:pharmacokinetics*; D014344:Trypanocidal Agents / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D009593:Nitroimidazoles; D014344:Trypanocidal Agents; C009999:benzonidazole
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