Bioavailability of a novel sustained‐release pellet formulation of 5‐flucytosine in healthy‐fed participants for use in patients with cryptococcal meningitis

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.