Stott, Katharine E 
ORCID: 0000-0001-7079-7957, Ahmadu, Ajisa, Kajanga, Cheusisime, Moyo, Melanie, Gondwe, Ebbie, Chimang'anga, Wezzie, Chasweka, Madalitso, Unsworth, Jennifer, Jimenez-Valverde, Ana ORCID: 0000-0003-4284-5629, Jagota, Bhavana et al (show 7 more authors)
(2023)
Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 78 (4).
pp. 1015-1022.
Abstract
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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).<h4>Conclusions</h4>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 |
|---|---|
| Uncontrolled Keywords: | Humans, Cryptococcus neoformans, Meningitis, Cryptococcal, HIV Infections, Meningoencephalitis, Flucytosine, Antifungal Agents, Bayes Theorem, Adult |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 02 Oct 2023 09:07 |
| Last Modified: | 02 Oct 2023 09:07 |
| DOI: | 10.1093/jac/dkad038 |
| Open Access URL: | https://doi.org/10.1093/jac/dkad038 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3173264 |
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