TY - JOUR
T1 - Bioavailability of a novel sustained-release pellet formulation of 5-flucytosine in healthy-fed participants for use in patients with cryptococcal meningitis
AU - Ibnou Zekri Lassout, Nabila
AU - Goyal, Vishal
AU - Krantz, Edrich
AU - Simon, Francois
AU - Neven, Anouk
AU - Eriksson, Johanna
AU - Saayman, Amaria
AU - Satam, Vijay
AU - Ruffell, Carol
AU - Victor, Sarika
AU - Chenel, Marylore
AU - Celebic, Aljosa
AU - Caplain, Henri
AU - Gillon, Jean Yves
AU - Deshmukh, Abhijit
AU - Antarkar, Amit
AU - Sjögren, Eric
AU - Ribeiro, Isabela
N1 - FUNDING INFORMATION
This project (grant RIA2018CO-2516) is part of the European and Developing Countries Clinical Trials Partnership Association (EDCTP2) program supported by the European Union, with additional funding from the Swiss Agency for Development and Cooperation (SDC), Switzerland; Médecins Sans Frontières International, and other private foundations and individuals.
Publisher Copyright:
© 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.
PY - 2024/9
Y1 - 2024/9
N2 - 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. Cmax 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.
AB - 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. Cmax 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.
UR - http://www.scopus.com/inward/record.url?scp=85204512527&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/39291723/
U2 - 10.1111/cts.13908
DO - 10.1111/cts.13908
M3 - Article
C2 - 39291723
AN - SCOPUS:85204512527
SN - 1752-8054
VL - 17
JO - Clinical and Translational Science
JF - Clinical and Translational Science
IS - 9
M1 - e13908
ER -