Influence of Experimental Cryptococcal Meningitis in Wistar Rats on Voriconazole Brain Penetration Assessed by Microdialysis [PublishAheadOfPrint]

To advance in the treatment of cryptococcal meningites is crucial to know the drug's free fraction that reaches the biophase. In the present study we applied the microdialysis (μD) as a tool to determine the free levels reached by voriconazole (VRC) in the brain of healthy and Cryptococcus neoformans infected rats. The infection was induced by the i.v. administration of 1⋅10⁵ CFU of yeast. The dose administered was 5 mg/kg i.v. of VRC. Plasma and microdialysate samples were analyzed by LC-MS/MS and LC-UV methods. The free brain/free plasma ratio (fT) and popPK analysis were performed to evaluate the impact of infection on PK parameters of the drug. The brain penetration ratio showed an increase on brain exposure in infected animals (fT_healthy = 0.85 vs fT_infected = 1.86). The structural PK model with two compartments and MM eliminating describes the VRC concentration-time profile in plasma and tissue simultaneously. The covariate infection was included in V₂ and V_M. Comparing the values observed in the tissue of infected and healthy animals, the levels reached in infected tissues were higher than the values described for MIC of VRC against Cryptococccus neoformans (0.03 -0.5 ug.mL^-1) indicating its great potential to treat meningitis associated to C. neoformans.

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