Luísa Perin1, Leonardo Pinto1, Glauco Henrique Balthazar Nardotto2, Kátia da Silva Fonseca1, Beatriz Oliveira Paiva1, Thaís Fernanda Rodrigues Bastos Mendes1, Israel Molina1,3, Rodrigo Correa-Oliveira1,4, Paula Melo de Abreu Vieira1,5, Cláudia Martins Carneiro1,6. 1. Laboratory of Immunopathology, Nucleus of Biological Sciences Research, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil. 2. Laboratory of Clinical Pharmacokinetics, Department of Clinical, Toxicological and Bromatological Analyses, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. 3. Tropical Medicine and International Health Unit, Department of Infectious Diseases, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain, PROSICS Barcelona. 4. Laboratory of Cellular and Molecular Immunology, René Rachou Research Center, Oswaldo Cruz Foundation, Belo Horizonte, Minas Gerais, Brazil. 5. Laboratory of Morphopathology, Department of Biological Sciences, Nucleus of Biological Sciences Research, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil. 6. Department of Clinical Analysis, School of Pharmacy, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
Abstract
OBJECTIVES: To evaluate the population pharmacokinetics of different benznidazole treatment regimens and the drug's biodistribution in mice. METHODS: Two hundred mice were divided into five groups according to benznidazole dosing regimens: (1) 100 mg/kg/day for 20 days; (2) 100 mg/kg/day for 40 days; (3) 200 mg/kg/day for 20 days; (4) 40 mg/kg/day for 20 days; or (5) 40 mg/kg/day for 40 days. The mice were euthanized and blood, heart, liver, colon and brain were collected. Samples were prepared by liquid-liquid extraction and analysed by HPLC-diode-array detection. The pharmacokinetic analysis of benznidazole was evaluated via non-linear mixed-effects modelling using the NONMEN program. RESULTS: Our results demonstrate that mouse weight allometrically influences benznidazole clearance; the AUC curve and the highest plasma concentration are dose proportional; benznidazole does not influence its own metabolism; its tissue distribution is limited; and the standard treatment regimen for Chagas' disease in mice (100 mg/kg/day for 20 days) is inadequate from a pharmacokinetic standpoint, as are the other regimens tested in this study (100 mg/kg/day for 40 days, 200 mg/kg/day for 20 days and 40 mg/kg/day for 20 or 40 days). CONCLUSIONS: Benznidazole reformulations that allow better tissue penetration and plasma and tissue exposure should be evaluated to enable higher cure rates in both animals and patients. The population pharmacokinetic model developed here can allow optimization of the dosing regimen of benznidazole to treat experimental Chagas' disease. Determining appropriate treatment regimens in animals allows translation of these to clinical studies.
OBJECTIVES: To evaluate the population pharmacokinetics of different benznidazole treatment regimens and the drug's biodistribution in mice. METHODS: Two hundred mice were divided into five groups according to benznidazole dosing regimens: (1) 100 mg/kg/day for 20 days; (2) 100 mg/kg/day for 40 days; (3) 200 mg/kg/day for 20 days; (4) 40 mg/kg/day for 20 days; or (5) 40 mg/kg/day for 40 days. The mice were euthanized and blood, heart, liver, colon and brain were collected. Samples were prepared by liquid-liquid extraction and analysed by HPLC-diode-array detection. The pharmacokinetic analysis of benznidazole was evaluated via non-linear mixed-effects modelling using the NONMEN program. RESULTS: Our results demonstrate that mouse weight allometrically influences benznidazole clearance; the AUC curve and the highest plasma concentration are dose proportional; benznidazole does not influence its own metabolism; its tissue distribution is limited; and the standard treatment regimen for Chagas' disease in mice (100 mg/kg/day for 20 days) is inadequate from a pharmacokinetic standpoint, as are the other regimens tested in this study (100 mg/kg/day for 40 days, 200 mg/kg/day for 20 days and 40 mg/kg/day for 20 or 40 days). CONCLUSIONS:Benznidazole reformulations that allow better tissue penetration and plasma and tissue exposure should be evaluated to enable higher cure rates in both animals and patients. The population pharmacokinetic model developed here can allow optimization of the dosing regimen of benznidazole to treat experimental Chagas' disease. Determining appropriate treatment regimens in animals allows translation of these to clinical studies.
Authors: Virgínia Paula Frade; Carlos Henrique Valente Moreira; Ester Cerdeira Sabino; Danilo César Galindo Bedor; Fábio de Rose Ghilard; Cláudia Di Lorenzo Oliveira; Cristina Sanches Journal: Rev Inst Med Trop Sao Paulo Date: 2022-02-02 Impact factor: 1.846
Authors: Kátia da Silva Fonseca; Luísa Perin; Nívia Carolina Nogueira de Paiva; Beatriz Cristiane da Silva; Thays Helena Chaves Duarte; Flávia de Souza Marques; Guilherme de Paula Costa; Israel Molina; Rodrigo Correa-Oliveira; Paula Melo de Abreu Vieira; Cláudia Martins Carneiro Journal: Pathogens Date: 2021-06-09