Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis
© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:78 |
|---|---|
| Enthalten in: |
The Journal of antimicrobial chemotherapy - 78(2023), 4 vom: 03. Apr., Seite 1015-1022 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Stott, Katharine E [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Antifungal Agents |
|---|
| Anmerkungen: |
Date Completed 04.04.2023 Date Revised 21.02.2024 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1093/jac/dkad038 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM35363462X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM35363462X | ||
| 003 | DE-627 | ||
| 005 | 20240222091234.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1093/jac/dkad038 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1301.xml |
| 035 | |a (DE-627)NLM35363462X | ||
| 035 | |a (NLM)36857467 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Stott, Katharine E |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 04.04.2023 | ||
| 500 | |a Date Revised 21.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Flucytosine |2 NLM | |
| 650 | 7 | |a D83282DT06 |2 NLM | |
| 650 | 7 | |a Antifungal Agents |2 NLM | |
| 700 | 1 | |a Ahmadu, Ajisa |e verfasserin |4 aut | |
| 700 | 1 | |a Kajanga, Cheusisime |e verfasserin |4 aut | |
| 700 | 1 | |a Moyo, Melanie |e verfasserin |4 aut | |
| 700 | 1 | |a Gondwe, Ebbie |e verfasserin |4 aut | |
| 700 | 1 | |a Chimang'anga, Wezzie |e verfasserin |4 aut | |
| 700 | 1 | |a Chasweka, Madalitso |e verfasserin |4 aut | |
| 700 | 1 | |a Unsworth, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Jimenez-Valverde, Ana |e verfasserin |4 aut | |
| 700 | 1 | |a Jagota, Bhavana |e verfasserin |4 aut | |
| 700 | 1 | |a Shah, Reya V |e verfasserin |4 aut | |
| 700 | 1 | |a Lawrence, David S |e verfasserin |4 aut | |
| 700 | 1 | |a Lalloo, David G |e verfasserin |4 aut | |
| 700 | 1 | |a Harrison, Tom |e verfasserin |4 aut | |
| 700 | 1 | |a Jarvis, Joseph N |e verfasserin |4 aut | |
| 700 | 1 | |a Hope, William |e verfasserin |4 aut | |
| 700 | 1 | |a Mwandumba, Henry C |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The Journal of antimicrobial chemotherapy |d 1981 |g 78(2023), 4 vom: 03. Apr., Seite 1015-1022 |w (DE-627)NLM000017701 |x 1460-2091 |7 nnns |
| 773 | 1 | 8 | |g volume:78 |g year:2023 |g number:4 |g day:03 |g month:04 |g pages:1015-1022 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1093/jac/dkad038 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 78 |j 2023 |e 4 |b 03 |c 04 |h 1015-1022 | ||