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Bioavailability of a novel sustained-release pellet formulation of 5-flucytosine in healthy-fed participants for use in patients with cryptococcal meningitis.
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- معلومة اضافية
- المصدر:
Publisher: WileyBlackwell Pub Country of Publication: United States NLM ID: 101474067 Publication Model: Print Cited Medium: Internet ISSN: 1752-8062 (Electronic) Linking ISSN: 17528054 NLM ISO Abbreviation: Clin Transl Sci Subsets: MEDLINE
- بيانات النشر:
Original Publication: Malden, MA : WileyBlackwell Pub., 2008-
- الموضوع:
- نبذة مختصرة :
Cryptococcal meningoencephalitis (CM) is an opportunistic fungal infection and a major cause of death among people living with human immunodeficiency virus in sub-Saharan Africa. 5-flucytosine (5-FC) is a unique, brain-permeable antifungal agent used to reduce mortality from CM and to prevent disease in individuals carrying cryptococcal antigen. 5-FC has a short plasma half-life, requiring 6-hourly oral dosing with an immediate-release (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-FC. In this phase I study, we assessed the safety and pharmacokinetic profiles of the new 5-FC SR formulation in a single dose (2 × 3000 mg), relative to 5-FC IR tablets (Ancotil®; 1500 mg b.i.d.) in healthy participants in fed conditions. This randomized, two-period crossover study was conducted in South Africa to confirm the dose of the identified 5-FC SR formulation for a twice-daily 5-FC regimen in patients. Thirty-six healthy participants were included. All treatments were well tolerated and no serious adverse event was reported. C max and AUC (0-t) for the SR formulation (49.2 ± 10.49 μg/mL and 640.4 ± 126.4 h.μg/mL, respectively) were significantly higher than for the IR formulation (36.8 ± 7.61 μg/mL and 456.6 ± 72.8 h.μg/mL, respectively). A physiological based pharmacokinetic model (PBPK) predicted that under fasting conditions, 6000 mg SR pellets would show a good overlap with the IR product (3000 mg b.i.d), thus 6000 mg SR 5-FC b.i.d. in fasting conditions is recommended.
(© 2024 Farmovs (Pty) Ltd, Luxembourg Institute of Health, Mylan Laboratories Ltd, Pharmetheus AB, Drugs for Neglected Diseases Initiative, DNDi GARDP Southern Africa NPC. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- References:
Lancet Infect Dis. 2024 Jul;24(7):e428-e438. (PMID: 38224705)
Clin Transl Sci. 2024 Sep;17(9):e13908. (PMID: 39291723)
Antimicrob Agents Chemother. 1978 Dec;14(6):903-8. (PMID: 742878)
J Antimicrob Chemother. 2000 May;45(5):645-9. (PMID: 10797087)
Antimicrob Agents Chemother. 1972 Jun;1(6):476-82. (PMID: 4680811)
N Engl J Med. 2024 Feb 8;390(6):487-489. (PMID: 38314820)
Lancet Infect Dis. 2022 Dec;22(12):1748-1755. (PMID: 36049486)
J Infect Dis. 1975 Oct;132(4):368-73. (PMID: 1185007)
J Antimicrob Chemother. 2000 Aug;46(2):171-9. (PMID: 10933638)
N Engl J Med. 2018 Mar 15;378(11):1004-1017. (PMID: 29539274)
AIDS. 2012 Jul 17;26(11):1363-70. (PMID: 22526517)
N Engl J Med. 1979 Jul 19;301(3):126-31. (PMID: 449951)
Clin Transl Sci. 2024 Mar;17(3):e13756. (PMID: 38488418)
Antimicrob Agents Chemother. 2010 Mar;54(3):1237-41. (PMID: 20038612)
Emerg Infect Dis. 2004 Jan;10(1):143-5. (PMID: 15078612)
- الرقم المعرف:
D83282DT06 (Flucytosine)
0 (Delayed-Action Preparations)
0 (Antifungal Agents)
- الموضوع:
Date Created: 20240918 Date Completed: 20240918 Latest Revision: 20241004
- الموضوع:
20250114
- الرقم المعرف:
PMC11409195
- الرقم المعرف:
10.1111/cts.13908
- الرقم المعرف:
39291723
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