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Stott, Katharine E, Ahmadu, Ajisa, Kajanga, Cheusisime, Moyo, Melanie, Gondwe, Ebbie, Chimang’anga, Wezzie, Chasweka, Madalitso, Unsworth, Jennifer, Jimenez-Valverde, Ana, Jagota, Bhavana, Shah, Reya V, Lawrence, David, Lalloo, David 
ORCID: https://orcid.org/0000-0001-7680-2200, Harrison, Tom, Jarvis, Joseph N, Hope, William and Mwandumba, Henry ORCID: https://orcid.org/0000-0003-4470-3608
(2023)
'Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis'. The Journal of Antimicrobial Chemotherapy, Vol 78, Issue 4, pp. 1015-1022.
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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 |
|---|---|
| Subjects: | WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503 Acquired immunodeficiency syndrome. HIV infections |
| Faculty: Department: | Clinical Sciences & International Health > Clinical Sciences Department |
| Digital Object Identifer (DOI): | https://doi.org/10.1093/jac/dkad038 |
| SWORD Depositor: | JISC Pubrouter |
| Depositing User: | JISC Pubrouter |
| Date Deposited: | 17 Mar 2023 13:47 |
| Last Modified: | 25 Apr 2023 12:42 |
| URI: | https://archive.lstmed.ac.uk/id/eprint/22112 |
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