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Influence of Experimental Cryptococcal Meningitis in Wistar Rats on Voriconazole Brain Penetration Assessed by
Izabel Almeida Alves1, Keli Jaqueline Staudt2, Carolina de Miranda Silva1
1Pharmaceutical Sciences Graduate Program of Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
Abstract:
To make advances in the treatment of cryptococcal meningitis, it is crucial to know a given drug's free fraction that reaches the biophase. In the present study, we applied microdialysis (μD) as a tool to determine the free levels reached by voriconazole (VRC) in the brains of healthy and Cryptococcus neoformans-infected rats. The infection was induced by the intravenous (i.v.) administration of 1 × 105 CFU of yeast. The dose administered was 5 mg/kg (of body weight) of VRC, given i.v. Plasma and microdialysate samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and LC-UV methods. The free brain/free plasma ratio (fT) and population pharmacokinetic (popPK) analyses 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 (fThealthy = 0.85 versus fTinfected = 1.86). The structural PK model with two compartments and Michaelis-Menten (MM) elimination describes the VRC concentration-time profile in plasma and tissue simultaneously. The covariate infection was included in volume of distribution in the peripheral compartment in healthy animals (V2) and maximum rate of metabolism (V ). The levels reached in infected tissues were higher than the values described for MIC of VRC for Cryptococccus neoformans (0.03 to 0.5 μg ml-1), indicating its great potential to treat meningitis associated with C. neoformans.
Insights
Voriconazole (VRC) shows increased brain penetration in rats with cryptococcal meningitis. This enhanced drug exposure suggests VRC
Area of Science:
- Pharmacology
- Infectious Diseases
- Neuroscience
Background:
- Cryptococcal meningitis treatment requires understanding drug penetration into the brain.
- Voriconazole (VRC) is a key antifungal, but its brain pharmacokinetics are not fully understood.
Purpose of the Study:
- To quantify VRC's free brain levels in healthy and Cryptococcus neoformans-infected rats.
- To assess the impact of infection on VRC's pharmacokinetic parameters.
Main Methods:
- Microdialysis (μD) was used to measure free VRC concentrations in rat brains.
- Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and LC-UV analyzed plasma and microdialysate samples.
- Population pharmacokinetic (popPK) modeling evaluated infection's effect on VRC pharmacokinetics.
Main Results:
- The free brain/free plasma ratio (fT) increased significantly in infected rats (1.86) compared to healthy rats (0.85).
- Population pharmacokinetic analysis revealed infection alters VRC's volume of distribution and metabolism.
- Achieved VRC concentrations in infected brain tissue exceeded the minimum inhibitory concentration (MIC) for Cryptococcus neoformans.
Conclusions:
- Voriconazole exhibits enhanced brain penetration during cryptococcal meningitis in rats.
- These findings support voriconazole's potential as an effective treatment for cryptococcal meningitis.
- Understanding VRC pharmacokinetics is crucial for optimizing antifungal therapy.
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