Population Pharmacokinetic Modeling to Describe the Total Plasma and Free Brain Levels of Fluconazole in Healthy and Cryptococcus neoformans Infected Rats: How Does the Infection Impact the Drug’s Levels on Biophase?

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 (1.10 5 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.