{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T12:28:57Z","timestamp":1753878537295,"version":"3.41.2"},"reference-count":20,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T00:00:00Z","timestamp":1726617600000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cryptococcal meningoencephalitis (CM) is an opportunistic fungal infection and a major cause of death among people living with human immunodeficiency virus in sub\u2010Saharan Africa. 5\u2010flucytosine (5\u2010FC) is a unique, brain\u2010permeable antifungal agent used to reduce mortality from CM and to prevent disease in individuals carrying cryptococcal antigen. 5\u2010FC has a short plasma half\u2010life, requiring 6\u2010hourly oral dosing with an immediate\u2010release (IR) formulation, a significant challenge in hospital and outpatient settings, risking a lack of compliance. We recently reported the relative bioavailability in fasting conditions of a sustained release (SR) oral pellet formulation of 5\u2010FC. In this phase I study, we assessed the safety and pharmacokinetic profiles of the new 5\u2010FC SR formulation in a single dose (2\u2009\u00d7\u20093000\u2009mg), relative to 5\u2010FC IR tablets (Ancotil\u00ae; 1500\u2009mg b.i.d.) in healthy participants in fed conditions. This randomized, two\u2010period crossover study was conducted in South Africa to confirm the dose of the identified 5\u2010FC SR formulation for a twice\u2010daily 5\u2010FC regimen in patients. Thirty\u2010six healthy participants were included. All treatments were well tolerated and no serious adverse event was reported. <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> and AUC<jats:sub>(0\u2013<jats:italic>t<\/jats:italic>)<\/jats:sub> for the SR formulation (49.2\u2009\u00b1\u200910.49 \u03bcg\/mL and 640.4\u2009\u00b1\u2009126.4\u2009h.\u03bcg\/mL, respectively) were significantly higher than for the IR formulation (36.8\u2009\u00b1\u20097.61 \u03bcg\/mL and 456.6\u2009\u00b1\u200972.8\u2009h.\u03bcg\/mL, respectively). A physiological based pharmacokinetic model (PBPK) predicted that under fasting conditions, 6000\u2009mg SR pellets would show a good overlap with the IR product (3000\u2009mg b.i.d), thus 6000\u2009mg SR 5\u2010FC b.i.d. in fasting conditions is recommended.<\/jats:p>","DOI":"10.1111\/cts.13908","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T10:55:22Z","timestamp":1726656922000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Bioavailability of a novel sustained\u2010release pellet formulation of 5\u2010flucytosine in healthy\u2010fed participants for use in patients with cryptococcal meningitis"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5554-0362","authenticated-orcid":false,"given":"Nabila","family":"Ibnou Zekri Lassout","sequence":"first","affiliation":[{"name":"Drugs for Neglected Diseases Initiative  Geneva 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Statistics (CCMS) Luxembourg Institute of Health  Strassen Luxembourg"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9921-0969","authenticated-orcid":false,"given":"Johanna","family":"Eriksson","sequence":"additional","affiliation":[{"name":"Pharmetheus  Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amaria","family":"Saayman","sequence":"additional","affiliation":[{"name":"FARMOVS  Bloemfontein South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vijay","family":"Satam","sequence":"additional","affiliation":[{"name":"Drugs for Neglected Diseases initiative  New Delhi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3180-7574","authenticated-orcid":false,"given":"Carol","family":"Ruffell","sequence":"additional","affiliation":[{"name":"DNDi GARDP Southern Africa  Cape Town South 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