Izabel Almeida Alves1, Keli Jaqueline Staudt2, Fernando Olinto Carreño1, Graziela de Araujo Lock1, Carolina de Miranda Silva1, Stela Maris Kuze Rates1, Teresa Dalla Costa1, Bibiana Verlindo De Araujo3,4. 1. Pharmaceutical Sciences Graduate Program of Federal University of Rio Grande do Sul, Av. Ipiranga, 2752, Porto Alegre, RS, 90610-000, Brazil. 2. Medical Sciences Graduate Program of Federal University of Rio Grande do Sul, Av. Ipiranga 2752, office 407, Porto Alegre, RS, 90610-000, Brazil. 3. Pharmaceutical Sciences Graduate Program of Federal University of Rio Grande do Sul, Av. Ipiranga, 2752, Porto Alegre, RS, 90610-000, Brazil. bibiana.araujo@ufrgs.br. 4. Medical Sciences Graduate Program of Federal University of Rio Grande do Sul, Av. Ipiranga 2752, office 407, Porto Alegre, RS, 90610-000, Brazil. bibiana.araujo@ufrgs.br.
Abstract
PURPOSE: The present work aimed to evaluate the influence of experimental meningitis caused by C. neoformans on total plasma and free brain concentrations of fluconazole (FLC) in Wistar rats. METHOD: The infection was induced by the administration of 100 μL of inoculum (1.105 CFU) through the tail vein. Free drug in the brain was assessed by microdialisys (μD). Blood and μD samples were collected at pre-determined time points up to 12 h after intravenous administration of FLC (20 mg/kg) to healthy and infected rats. The concentration-time profiles were analyzed by non-compartmental and population pharmacokinetics approaches. RESULTS: A two-compartmental popPK model was able to simultaneously describe plasma and free drug concentrations in the brain for both groups investigated. Analysis of plasma and μD samples showed a better FLC distribution on the brain of infected than healthy animals (1.04 ± 0.31 vs 0.69 ± 0.14, respectively). The probability of target attainment was calculated by Monte Carlo simulations based on the developed popPK model for 125 mg/kg dose for rats and 400-2000 mg for humans. CONCLUSIONS: FLC showed a limited use in monotherapy to the treatment of criptoccocosis in rats and humans to value of MIC >8 μg/mL.
PURPOSE: The present work aimed to evaluate the influence of experimental meningitis caused by C. neoformans on total plasma and free brain concentrations of fluconazole (FLC) in Wistar rats. METHOD: The infection was induced by the administration of 100 μL of inoculum (1.105 CFU) through the tail vein. Free drug in the brain was assessed by microdialisys (μD). Blood and μD samples were collected at pre-determined time points up to 12 h after intravenous administration of FLC (20 mg/kg) to healthy and infected rats. The concentration-time profiles were analyzed by non-compartmental and population pharmacokinetics approaches. RESULTS: A two-compartmental popPK model was able to simultaneously describe plasma and free drug concentrations in the brain for both groups investigated. Analysis of plasma and μD samples showed a better FLC distribution on the brain of infected than healthy animals (1.04 ± 0.31 vs 0.69 ± 0.14, respectively). The probability of target attainment was calculated by Monte Carlo simulations based on the developed popPK model for 125 mg/kg dose for rats and 400-2000 mg for humans. CONCLUSIONS:FLC showed a limited use in monotherapy to the treatment of criptoccocosis in rats and humans to value of MIC >8 μg/mL.
Entities:
Keywords:
Cryptococcus neoformans; fluconazole; infection; meningitis; microdialysis; monte Carlo simulations; poppk model
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