title: Determination of an optimal dosing regimen for fexinidazole, a novel oral drug for the treatment of human African trypanosomiasis: first-in-human studies.
abstract: OBJECTIVE
  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.
authors.affiliation: Drugs for Neglected Diseases Initiative (DNDi), 15 Chemin Louis-Dunant, 1202, Geneva, Switzerland, atarral@dndi.org.
authors.forename: Antoine
authors.initials: A
authors.lastname: Tarral
authors.forename: Séverine
authors.initials: S
authors.lastname: Blesson
authors.forename: Olaf Valverde
authors.initials: OV
authors.lastname: Mordt
authors.forename: Els
authors.initials: E
authors.lastname: Torreele
authors.forename: Daniela
authors.initials: D
authors.lastname: Sassella
authors.forename: Michael A
authors.initials: MA
authors.lastname: Bray
authors.forename: Lionel
authors.initials: L
authors.lastname: Hovsepian
authors.forename: Eric
authors.initials: E
authors.lastname: Evène
authors.forename: Virginie
authors.initials: V
authors.lastname: Gualano
authors.forename: Mathieu
authors.initials: M
authors.lastname: Felices
authors.forename: Nathalie
authors.initials: N
authors.lastname: Strub-Wourgaft
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D018592:Cross-Over Studies; D004041:Dietary Fats / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D009593:Nitroimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011355:Prodrugs; D013535:Suspensions; D013607:Tablets; D014344:Trypanocidal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014353:Trypanosomiasis, African / Q000188:drug therapy; D055815:Young Adult
chemical_list: D004041:Dietary Fats; D009593:Nitroimidazoles; D011355:Prodrugs; D013535:Suspensions; D013607:Tablets; D014344:Trypanocidal Agents; C038307:fexinidazole