{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T08:32:28Z","timestamp":1782203548040,"version":"3.54.5"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T00:00:00Z","timestamp":1677628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005564","name":"Gilead Sciences","doi-asserted-by":"crossref","award":["IN-EU-131-D036"],"award-info":[{"award-number":["IN-EU-131-D036"]}],"id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001713","name":"European Developing Countries Clinical Trials Partnership","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001713","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004441","name":"Swedish International Development Cooperation Agency","doi-asserted-by":"crossref","award":["TRIA2015-1092"],"award-info":[{"award-number":["TRIA2015-1092"]}],"id":[{"id":"10.13039\/100004441","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["MR\/P006922\/1"],"award-info":[{"award-number":["MR\/P006922\/1"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["203919\/Z\/16\/Z"],"award-info":[{"award-number":["203919\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"crossref","award":["RP-2017-08-ST2-012"],"award-info":[{"award-number":["RP-2017-08-ST2-012"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"crossref"}]},{"name":"DFID","award":["MR\/P020526\/1"],"award-info":[{"award-number":["MR\/P020526\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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\u2013168 h) with doses of 25 mg\/kg q6h were median (IQR) 890.38 (603.81\u20131213.70) mg.h\/L in plasma and 595.66 (425.69\u2013776.64) mg.h\/L in CSF. The ratio of CSF:plasma AUC24 was 0.69 (IQR 0.58\u20130.82).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1093\/jac\/dkad038","type":"journal-article","created":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T19:14:32Z","timestamp":1677698072000},"page":"1015-1022","source":"Crossref","is-referenced-by-count":13,"title":["Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis"],"prefix":"10.1093","volume":"78","author":[{"given":"Katharine E","family":"Stott","sequence":"first","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool , Liverpool , UK"},{"name":"Malawi Liverpool Wellcome Trust Clinical Research Programme , Blantyre , Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajisa","family":"Ahmadu","sequence":"additional","affiliation":[{"name":"Malawi Liverpool Wellcome Trust Clinical Research Programme , Blantyre , Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheusisime","family":"Kajanga","sequence":"additional","affiliation":[{"name":"Malawi Liverpool Wellcome Trust Clinical Research Programme , Blantyre , Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Moyo","sequence":"additional","affiliation":[{"name":"Malawi Liverpool Wellcome Trust Clinical Research Programme , Blantyre , Malawi"},{"name":"Department of Medicine, Kamuzu University of Health Sciences , Blantyre , Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebbie","family":"Gondwe","sequence":"additional","affiliation":[{"name":"Malawi Liverpool Wellcome Trust Clinical Research Programme , Blantyre , Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wezzie","family":"Chimang\u2019anga","sequence":"additional","affiliation":[{"name":"Malawi Liverpool Wellcome Trust Clinical Research Programme , Blantyre , Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madalitso","family":"Chasweka","sequence":"additional","affiliation":[{"name":"Malawi Liverpool Wellcome Trust Clinical Research Programme , Blantyre , Malawi"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Unsworth","sequence":"additional","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool , Liverpool , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Jimenez-Valverde","sequence":"additional","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool , Liverpool , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhavana","family":"Jagota","sequence":"additional","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool , Liverpool , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reya V","family":"Shah","sequence":"additional","affiliation":[{"name":"Institute for Infection and Immunity, St George\u2019s University London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S","family":"Lawrence","sequence":"additional","affiliation":[{"name":"Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine , London , UK"},{"name":"Botswana Harvard AIDS Institute Partnership , Gaborone , Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G","family":"Lalloo","sequence":"additional","affiliation":[{"name":"Liverpool School of Tropical Medicine , Liverpool , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Harrison","sequence":"additional","affiliation":[{"name":"Clinical Academic Group in Infection, St George\u2019s University Hospitals NHS Foundation Trust , London , UK"},{"name":"MRC Centre for Medical Mycology, University of Exeter , Exeter , UK"},{"name":"Department of Clinical Sciences, Liverpool School of Tropical Medicine , Liverpool , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph N","family":"Jarvis","sequence":"additional","affiliation":[{"name":"Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine , London , UK"},{"name":"Botswana Harvard AIDS Institute Partnership , Gaborone , Botswana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Hope","sequence":"additional","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, University of Liverpool , Liverpool , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry C","family":"Mwandumba","sequence":"additional","affiliation":[{"name":"Malawi Liverpool Wellcome Trust Clinical Research Programme , Blantyre , Malawi"},{"name":"Department of Medicine, Kamuzu University of Health Sciences , Blantyre , Malawi"},{"name":"Department of Clinical Sciences, Liverpool School of Tropical Medicine , Liverpool , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,3,1]]},"reference":[{"key":"2023040308032077600_","doi-asserted-by":"crossref","first-page":"4559","DOI":"10.1021\/ja01573a087","article-title":"The synthesis of 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