Population pharmacokinetics and cerebrospinal fluid penetration of fluconazole in adults with cryptococcal meningitis
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...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Society for Microbiology
2018
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| _version_ | 1826257567645433856 |
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| author | Stott, K Beardsley, J Kolamunnage-Dona, R Santoyo Castelazo, A Kibengo, F Mai, N Day, J Hope, W |
| author_facet | Stott, K Beardsley, J Kolamunnage-Dona, R Santoyo Castelazo, A Kibengo, F Mai, N Day, J Hope, W |
| author_sort | Stott, K |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T18:20:16Z |
| format | Journal article |
| id | oxford-uuid:060b1823-ec56-402d-be69-45fd086754f8 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:20:16Z |
| publishDate | 2018 |
| publisher | American Society for Microbiology |
| record_format | dspace |
| spelling | oxford-uuid:060b1823-ec56-402d-be69-45fd086754f82022-03-26T09:00:26ZPopulation pharmacokinetics and cerebrospinal fluid penetration of fluconazole in adults with cryptococcal meningitisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:060b1823-ec56-402d-be69-45fd086754f8EnglishSymplectic Elements at OxfordAmerican Society for Microbiology2018Stott, KBeardsley, JKolamunnage-Dona, RSantoyo Castelazo, AKibengo, FMai, NDay, JHope, WRobust 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. |
| spellingShingle | Stott, K Beardsley, J Kolamunnage-Dona, R Santoyo Castelazo, A Kibengo, F Mai, N Day, J Hope, W Population pharmacokinetics and cerebrospinal fluid penetration of fluconazole in adults with cryptococcal meningitis |
| title | Population pharmacokinetics and cerebrospinal fluid penetration of fluconazole in adults with cryptococcal meningitis |
| title_full | Population pharmacokinetics and cerebrospinal fluid penetration of fluconazole in adults with cryptococcal meningitis |
| title_fullStr | Population pharmacokinetics and cerebrospinal fluid penetration of fluconazole in adults with cryptococcal meningitis |
| title_full_unstemmed | Population pharmacokinetics and cerebrospinal fluid penetration of fluconazole in adults with cryptococcal meningitis |
| title_short | Population pharmacokinetics and cerebrospinal fluid penetration of fluconazole in adults with cryptococcal meningitis |
| title_sort | population pharmacokinetics and cerebrospinal fluid penetration of fluconazole in adults with cryptococcal meningitis |
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