title: Systematic Review and Meta-analysis of the Pharmacokinetics of Benznidazole in the Treatment of Chagas Disease.
abstract: Chagas disease is a neglected parasitic illness affecting approximately 8 million people, predominantly in Latin America. Benznidazole is the drug of choice for treatment, although its availability has been limited. A paucity of knowledge of the pharmacokinetic properties of this drug has contributed to its limited availability in several jurisdictions. The objective of this study was to conduct a systematic literature review and a Bayesian meta-analysis of pharmacokinetic studies to improve estimates of the basic pharmacokinetic properties of benznidazole. A systematic search of the Embase, Medline, LILACS, and SciELO (Scientific Electronic Library Online) databases was conducted. Eligible studies reported patient-level data from single-100-mg-dose pharmacokinetic evaluations of benznidazole in adults or otherwise provided data relevant to the estimation of pharmacokinetic parameters which could be derived from such studies. A Bayesian hierarchical model was used for analysis. Secondary data (i.e., data from studies that did not include patient-level, single-100-mg-dose data) were used for the generation of empirical priors for the Bayesian analysis. The systematic search identified nine studies for inclusion. Nine pharmacokinetic parameters were estimated, including the area under the concentration-time curve (AUC), the maximum concentration of drug in plasma (Cmax), the time to Cmax, the elimination rate constant (kel), the absorption rate constant (Ka), the absorption and elimination half-lives, the apparent oral clearance, and the apparent oral volume of distribution. The results showed consistency across studies. AUC and Cmaxwere 51.31 mg · h/liter (95% credible interval [CrI], 45.01, 60.28 mg · h/liter) and 2.19 mg/liter (95% CrI, 2.06, 2.33 mg/liter), respectively. Kaand kelwere 1.16 h-1(95% CrI, 0.59, 1.76 h-1) and 0.052 h-1(95% CrI, 0.045, 0.059 h-1), respectively, with the corresponding absorption and elimination half-lives being 0.60 h (95% CrI, 0.38, 1.11 h) and 13.27 h (95% CrI, 11.79, 15.42 h), respectively. The oral clearance and volume of distribution were 2.04 liters/h (95% CrI, 1.77, 2.32 liters/h) and 39.19 liters (95% CrI, 36.58, 42.17 liters), respectively. A Bayesian meta-analysis was used to improve the estimates of the standard pharmacokinetic parameters of benznidazole. These data can inform clinicians and policy makers as access to this drug increases.
authors.affiliation: Precision Global Health, Vancouver, British Columbia, Canada.|Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Matthew O
authors.identifier: 0000-0002-3287-5181
authors.initials: MO
authors.lastname: Wiens
authors.affiliation: Precision Global Health, Vancouver, British Columbia, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Kanters
authors.affiliation: Precision Global Health, Vancouver, British Columbia, Canada.|Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Edward
authors.initials: E
authors.lastname: Mills
authors.affiliation: Departamento de Farmacobiología, Centro Universitario de Ciencias Exactas e Ingenierías, Universidad de Guadalajara, Guadalajara, Jalisco, México.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Peregrina Lucano
authors.affiliation: Fundación Mundo Sano, Buenos Aires, Argentina.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gold
authors.affiliation: Precision Global Health, Vancouver, British Columbia, Canada.
authors.forename: Dieter
authors.initials: D
authors.lastname: Ayers
authors.affiliation: Fundación Mundo Sano, Buenos Aires, Argentina.
authors.forename: Luis
authors.initials: L
authors.lastname: Ferrero
authors.affiliation: Instituto de Investigaciones en Enfermedades Tropicales and Instituto de Patologia Experimental, Universidad Nacional de Salta/CONICET, Salta, Argentina alekrol@hotmail.com.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Krolewiecki
mesh_terms: D019540:Area Under Curve; D014355:Chagas Disease / Q000188:drug therapy*; D006801:Humans; D009593:Nitroimidazoles / Q000097:blood / Q000493:pharmacokinetics*; D014344:Trypanocidal Agents / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D009593:Nitroimidazoles; D014344:Trypanocidal Agents; C009999:benzonidazole