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

Abstract

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.

FIGURE 1

Simulated and observed 5‐FC plasma concentration–time profiles in (a) fasted and (b) fed state. Immediate‐release formulation dosing was 1500 mg at t = 0 h and t = 6 h and sustained‐release formulation dosing was 3000 mg at t = 0 h. Observations from the 35 enrolled patients in the first phase I study are represented by dots. The solid line and shaded area represent the simulated geometric mean and the 5–95% quantiles of the PBPK model for a virtual population (n = 200). Below limits of quantification (BLQ) values removed from the plot.

FIGURE 2

Study flow chart. Each participant received the two treatments (5‐FC immediate release and 5‐FC sustained release), with washout periods (crossover design), in randomized order. IMP, investigational medicinal product, PK, pharmacokinetic.

FIGURE 3

Flucytosine (5‐FC) plasma concentrations for the 5‐FC immediate release (IR) tablets (reference product) (two doses, 1500 mg each, 6 h apart) and the 5‐FC sustained release (SR) formulations (one dose of 6000 mg) in individual participants. The red line represents the geometric mean.

FIGURE 4

Estimated PK parameters at steady state in fasted conditions for an immediate‐release formulation and sustained‐released formulation in all participants grouped by body weight. Weight‐based dosing is 100 mg/kg/day (divided into four dosing occasions/day) for the immediate‐release formulation and sustained‐release formulation dosing is 6000 mg b.i.d. MIC₉₀ is represented by the dotted line. The boxplots show the median represented by the central line in the box, the box edges represent the 25th and 75th percentile, the lower and upper whiskers represent the smallest and largest values within 1.5 times the interquartile range, respectively, and the dots represent the outliers as defined by >1.5 times or <3 times the interquartile range.

FIGURE 5

Simulated 5‐FC plasma concentration–time profiles up to steady state in fasted and fed state for a participant of 60 kg. Black (immediate‐release treatment) and colored (sustained‐release treatment) lines and shaded areas represent the median and 5%–95% range of the simulations, respectively. Immediate‐release formulation dosing was 1500 mg four times per day and sustained‐release formulation dosing was 6000 mg b.i.d. The dashed lines represent the therapeutic interval and the dotted line represents MIC₉₀.