| Summary: | Robust population pharmacokinetic (PK) data for fluconazole are scarce. The variability of fluconazole penetration into the CNS is not known. A fluconazole PK study was conducted in 43 patients receiving oral fluconazole (usually 800 mg q24h) in combination with amphotericin B deoxycholate (1 mg/kg q24h) for cryptococcal meningitis (CM). A 4-compartment PK model was developed and Monte Carlo simulations performed for a range of fluconazole dosages. A meta-analysis of trials reporting outcomes of CM patients treated with fluconazole monotherapy was performed. Adjusted for bioavailability, the PK parameter means (standard deviation) were: clearance, 0.72 (0.24) litres/hour; volume of the central compartment, 18.07 (6.31) litres; volume of central nervous system (CNS) compartment, 32.07 (17.60) litres; first-order rate constant from central to peripheral compartment, 12.20 (11.17) hours-1; from peripheral to central compartment, 18.10 (8.25) hours-1; from central to CNS compartment 35.43 (13.74) hours-1; from CNS to central compartment 28.63 (10.03) hours-1 Simulations of area under concentration-time curve resulted in median (interquartile range) values 1143.2 mg.h/litre (988.4 - 1378.0) in plasma and 982.9 (781.0 - 1185.9) in CSF after a dosage of 1200mg q24h. The mean simulated ratio of AUCCSF:AUCplasma was 0.89 (SD 0.44). The recommended dosage of fluconazole for CM induction therapy fails to attain the PD target in respect to the wild-type MIC distribution of C. neoformans The meta-analysis suggested modest improvements in both CSF sterility and mortality outcomes with escalating dosage. This study provides the pharmacodynamic rationale for the long-recognised fact that fluconazole monotherapy is an inadequate induction regimen for CM.
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