Bioavailability of three novel oral, sustained-release pellets, relative to an immediate-release tablet containing 500 mg flucytosine: A randomized, open-label, crossover study in healthy volunteers

Abstract

The opportunistic fungal infection cryptococcal meningoencephalitis is a major cause of death among people living with HIV in sub-Saharan Africa. We report pharmacokinetic (PK) and safety data from a randomized, four-period crossover phase I trial of three sustained-release (SR) oral pellet formulations of 5-flucytosine conducted in South Africa. These formulations were developed to require less frequent administration, to provide a convenient alternative to the current immediate release (IR) formulation, A. Formulations B, C, and D were designed to release 5-flucytosine as a percentage of the nominal dose in vitro. We assessed their safety and PK profiles in a single dose (1 × 3000 mg at 0 h), relative to commercial IR tablets (Ancotil 500 mg tablets; 3 × 500 mg at 0 h and 3 × 500 mg at 6 h) in healthy, fasted participants. Forty-two healthy participants were included. All treatments were well-tolerated. The primary PK parameters, maximum observed plasma concentration (C_max ) and area under the concentration-time profiles, were significantly lower for the SR formulations than for the IR tablets, and the geometric mean ratios fell outside the conventional bioequivalence limits. The median maximum time to C_max was delayed for the SR pellets. Physiologically-based PK modeling indicated a twice-daily 6400 mg dose of SR formulation D in fasted condition would be optimal for further clinical development. This regimen is predicted to result in a rapid steady-state plasma exposure with effective and safe trough plasma concentration and C_max values, within the therapeutic boundaries relative to plasma exposure after four times per day administration of IR tablets (PACTR202201760181404).

FIGURE 1

Study flow chart. Each participant received the four treatments, with wash‐out periods (cross‐over design), in randomized order. IMP, investigational medicinal product, PK, pharmacokinetic.

FIGURE 2

Flucytosine plasma concentrations for the IR reference tablets (2 doses, 1500 mg each, 6 h apart) and three SR formulations (B, C, D; 3000 mg) in individual volunteers. The red line represents the geometric mean. PK sampling was conducted over 48 h. The IR plasma profile was characterized by the presence of two relatively sharp peaks (explained by the 2 dosings for the IR treatment), followed by a steep decline. On the other hand, the plasma concentration‐time profile of the SR pellets was characterized by a gradual increase to a single peak, followed by a gradual decline. IR, immediate‐release; PK, pharmacokinetic; SR, sustained‐release.

FIGURE 3

Arithmetic mean flucytosine plasma concentrations on linear scales for the IR reference tablets (two doses, 1500 mg each, 6 h apart) and three sustained‐release formulations (B, C, D; 3000 mg). PK sampling was conducted over 48 h. The IR plasma profile was characterized by the presence of two relatively sharp peaks (explained by the two dosings for the IR treatment) followed by a steep decline, whereas the plasma concentration‐time profile of the SR pellets was characterized by a gradual increase to a single peak followed by a gradual decline. IR, immediate‐release; PK, pharmacokinetic; SR, sustained‐release.

FIGURE 4

Physiologically‐based pharmacokinetic modeling for plasma exposure of 5‐flucytosine for twice‐daily treatments B, C, or D in fed volunteers. Predicted dosing needed for each treatment to produce an acceptable C _trough between 20 and 70 mg/L and safe C _max < 100 mg/L when administered twice daily in fed state. C _max, maximum observed plasma concentration; C _trough, trough plasma concentration.