Determination of an Optimal Dosing Regimen for Fexinidazole, a Novel Oral Drug for the Treatment of Human African Trypanosomiasis: First-in-Human Studies

• Published in: Clinical pharmacokinetics Vol. 53; no. 6; pp. 565 - 580
• Main Authors: Tarral, Antoine, Blesson, Séverine, Mordt, Olaf Valverde, Torreele, Els, Sassella, Daniela, Bray, Michael A., Hovsepian, Lionel, Evène, Eric, Gualano, Virginie, Felices, Mathieu, Strub-Wourgaft, Nathalie
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-06-2014; Adis International; Springer Nature B.V
• Subjects: Administration, Oral; Adolescent; Adult; Biological and medical sciences; Biological Availability; Cross-Over Studies; Dietary Fats - administration & dosage; Dose-Response Relationship, Drug; Double-Blind Method; Food-Drug Interactions; General pharmacology; Human protozoal diseases; Humans; Infectious diseases; Internal Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Nitroimidazoles - administration & dosage; Nitroimidazoles - adverse effects; Nitroimidazoles - pharmacokinetics; Original; Original Research Article; Parasitic diseases; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Prodrugs; Protozoal diseases; Suspensions; Tablets; Trypanocidal Agents - administration & dosage; Trypanocidal Agents - adverse effects; Trypanocidal Agents - pharmacokinetics; Trypanosomiasis; Trypanosomiasis, African - drug therapy; Young Adult; Melarsoprol; Human African Trypanosomiasis; Visceral Leishmaniasis; Nifurtimox; Eflornithine; Human; Protozoal disease; Fexinidazole; Oral administration; Parasitosis; African sickness; Posology; Infection; Chemotherapy; Treatment; Therapeutic protocol; Trypanosomiasis; Quantitative analysis
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-014-0136-3

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.