Population Pharmacokinetics and Cerebrospinal Fluid Penetration of Fluconazole in Adults with Cryptococcal Meningitis
Stott KE., Beardsley J., Kolamunnage-Dona R., Castelazo AS., Kibengo FM., Mai NTH., Day J., Hope W.
<jats:title>ABSTRACT</jats:title> <jats:p>Robust population pharmacokinetic (PK) data for fluconazole are scarce. The variability of fluconazole penetration into the central nervous system (CNS) is not known. A fluconazole PK study was conducted in 43 patients receiving oral fluconazole (usually 800 mg every 24 h [q24h]) in combination with amphotericin B deoxycholate (1 mg/kg q24h) for cryptococcal meningitis (CM). A four-compartment PK model was developed, and Monte Carlo simulations were 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 the following: clearance, 0.72 (0.24) liters/h; volume of the central compartment, 18.07 (6.31) liters; volume of the CNS compartment, 32.07 (17.60) liters; first-order rate constant from the central to peripheral compartment, 12.20 (11.17) h<jats:sup>−1</jats:sup>, from the peripheral to central compartment, 18.10 (8.25) h<jats:sup>−1</jats:sup>, from the central to CNS compartment, 35.43 (13.74) h<jats:sup>−1</jats:sup>, and from the CNS to central the compartment, 28.63 (10.03) h<jats:sup>−1</jats:sup>. Simulations of the area under concentration-time curve resulted in median (interquartile range) values of 1,143.2 (range, 988.4 to 1,378.0) mg · h/liter in plasma (AUC<jats:sub>plasma</jats:sub>) and 982.9 (range, 781.0 to 1,185.9) mg · h/liter in cerebrospinal fluid (AUC<jats:sub>CSF</jats:sub>) after a dosage of 1,200 mg q24h. The mean simulated ratio of AUC<jats:sub>CSF</jats:sub>/AUC<jats:sub>plasma</jats:sub> was 0.89 (standard deviation [SD], 0.44). The recommended dosage of fluconazole for CM induction therapy fails to attain the pharmacodynamic (PD) target in respect to the wild-type MIC distribution for <jats:named-content content-type="genus-species">C. neoformans</jats:named-content>. 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-recognized fact that fluconazole monotherapy is an inadequate induction regimen for CM.</jats:p>