A 10 week, open-label, randomized, controlled parallel-group trial to evaluate the comparative bioavailability, efficacy and safety of sustained-release flucytosine versus immediate-release flucytosine in adults with cryptococcal meningitis

The current immediate-release (IR) 5FC formulation has a short half-life, necessitating dosing four times per day. To achieve clinically effective concentrations, the recommended daily dose is high (100 mg/kg/d) and the dosing regimen is sub-optimal: every 6 hours i.e., 4 times per day. Data show that the fourth dose in particular is often missed. In addition, this current formulation has not been developed or approved for nasogastric (NG) administration, necessary for patients with a reduced level of consciousness. A convenient and patient-adapted formulation, such as a sustained-released (SR) multi-particulate, pellet formulation, will greatly facilitate clinical practice by reducing the number of administrations per day, standardization of therapy, and potentially improving the concentration and exposure levels of 5FC over time. A SR 5FC formulation, which could be adapted to administration via NG tube and optimized for twice daily administration is considered an urgent priority to attain significant reductions in mortality and change the practice of medicine for Cryptococcal Meningitis.Primary PK Objective• To assess the primary bioavailability parameter (AUC0-t) of SR 5FC as compared to IR 5FC, administered in combination with L-AmB and fluconazolePrimary efficacy/PD Objective• To evaluate early fungicidal activity of SR 5FC, as compared to IR 5FC, administered in combination with L-AmB and fluconazoleSecondary objectivesSecondary PK Objectives• To assess the secondary bioavailability parameters (Cmax, Cmin, Cav, Cmax Cmin fluctuation, Tmax) of SR 5FC as compared to IR 5FC, administered in combination with L-AmB and fluconazole• To assess the safety of SR 5FC, as compared to IR 5FC, both administered in combination with L-AmB and fluconazole