Stott, KE;
Ahmadu, A;
Kajanga, C;
Moyo, M;
Gondwe, E;
Chimang'anga, W;
Chasweka, M;
Unsworth, J;
Jimenez-Valverde, A;
Jagota, B;
et al.
Stott, KE; Ahmadu, A; Kajanga, C; Moyo, M; Gondwe, E; Chimang'anga, W; Chasweka, M; Unsworth, J; Jimenez-Valverde, A; Jagota, B; Shah, RV; Lawrence, DS; Lalloo, DG; Harrison, T; Jarvis, JN; Hope, W; Mwandumba, HC
(2023)
Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis.
J Antimicrob Chemother, 78 (4).
pp. 1015-1022.
ISSN 1460-2091
https://doi.org/10.1093/jac/dkad038
SGUL Authors: Harrison, Thomas Stephen
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Abstract
BACKGROUND: There are limited data describing clinical flucytosine pharmacokinetics (PK). The variability of flucytosine partitioning into the CNS is not known. We described the interindividual variability in flucytosine PK in patients with HIV-associated cryptococcal meningoencephalitis. In addition, we quantified the extent and variability of CSF partitioning of flucytosine. METHODS: A PK study was conducted in 64 patients with confirmed HIV-associated cryptococcal meningoencephalitis in Blantyre, Malawi. A four-compartment PK model was developed, and Monte Carlo simulations were performed with flucytosine administered at different doses and in different schedules. RESULTS: The estimated mean apparent volume of the central compartment was 17.50 (SD 9.99) L; mean apparent clearance was 5.88 (SD 3.35) L/h; mean apparent volume of the CNS compartment was 41.73 (SD 13.66) L. From the Bayesian posterior estimates, AUC24 values at steady state (144-168 h) with doses of 25 mg/kg q6h were median (IQR) 890.38 (603.81-1213.70) mg.h/L in plasma and 595.66 (425.69-776.64) mg.h/L in CSF. The ratio of CSF:plasma AUC24 was 0.69 (IQR 0.58-0.82). CONCLUSIONS: This study revealed significant interindividual variability in flucytosine PK in plasma and CSF in patients with HIV-associated cryptococcal meningoencephalitis. The population PK model is a first critical step for revised flucytosine regimens that maximize fungal killing and minimize toxicity and the emergence of resistance.
Item Type: | Article | |||||||||||||||
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Additional Information: | © The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. | |||||||||||||||
Keywords: | Humans, Adult, Flucytosine, Antifungal Agents, Meningitis, Cryptococcal, Bayes Theorem, Meningoencephalitis, Cryptococcus neoformans, HIV Infections, Humans, Cryptococcus neoformans, Meningitis, Cryptococcal, HIV Infections, Meningoencephalitis, Flucytosine, Antifungal Agents, Bayes Theorem, Adult, 0605 Microbiology, 1108 Medical Microbiology, 1115 Pharmacology and Pharmaceutical Sciences, Microbiology | |||||||||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Infection and Immunity Research Institute (INII) | |||||||||||||||
Journal or Publication Title: | J Antimicrob Chemother | |||||||||||||||
ISSN: | 1460-2091 | |||||||||||||||
Language: | eng | |||||||||||||||
Dates: |
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Publisher License: | Creative Commons: Attribution 4.0 | |||||||||||||||
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PubMed ID: | 36857467 | |||||||||||||||
Web of Science ID: | WOS:000941861700001 | |||||||||||||||
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URI: | https://openaccess.sgul.ac.uk/id/eprint/115484 | |||||||||||||||
Publisher's version: | https://doi.org/10.1093/jac/dkad038 |
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