BACKGROUND AND OBJECTIVES: Fexinidazole is a 5-nitroimidazole recently included 
in a clinical efficacy trial as an oral drug for the treatment of human African 
trypanosomiasis (HAT). Preclinical studies showed it acts as a pharmacologically 
active pro-drug with two key active metabolites: sulfoxide and sulfone (the most 
active metabolite). The present studies aimed to determine the best dose regimen 
for the treatment of stage 2 sleeping sickness patients, which could eventually 
also treat stage 1 patients.
METHODS: Fexinidazole was assessed in 154 healthy adult male subjects of 
sub-Saharan African origin. Three initial first-in-human studies and two 
additional studies assessed a single ascending dose and multiple ascending doses 
(both under fasted conditions), tablet versus suspension formulation and food 
effect (fasted vs. high-fat meal and field-adapted food), and multiple ascending 
doses with a loading dose regimen under fed conditions.
RESULTS: Fexinidazole was well-tolerated in a single dose from 100 to 3,600 mg, 
with quick absorption of the parent drug and rapid metabolism into sulfoxide 
[time to maximum concentration (t max) 2-5 h] and sulfone (t max 18-24 h). The 
tablet formulation was approximately 25 % less bioavailable than the suspension, 
and food intake increased drug absorption and plasma concentrations of 
fexinidazole and its two metabolites by approximately 200 %. Fourteen-day 
multiple ascending dosing administered up to 3,600 mg/day in fasted conditions 
showed that fexinidazole was generally well-tolerated (mild to moderate, 
spontaneously reversible drug-related adverse events). Following the high-fat 
food effect finding, another study was conducted to evaluate the impact of a 
low-fat regimen closer to that of the target population, showing that the type 
of meal does not influence fexinidazole absorption. The last study showed that a 
loading dose of 1,800 mg/day for 4 days followed by a 1,200 mg/day regimen for 6 
days with a normal meal provided the desired exposure of fexinidazole and its 
metabolites, particularly sulfone, with good tolerability. Based on preclinical 
evidence from a chronic infection mouse model, systemic drug concentrations 
obtained are expected to be clinically effective in stage 2 HAT.
CONCLUSIONS: These studies show that fexinidazole can be safely assessed in 
patients as a potential oral cure for both stages of HAT.