title: First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials.
abstract: OBJECTIVE
  To assess the safety and pharmacokinetics of a new synthetic ozonide antimalarial, OZ439, in a first-in-man, double-blind study in healthy volunteers.
  
  
  METHODS
  OZ439 was administered as single oral daily doses of a capsule formulation (50-1200 mg) or an oral dispersion (400-1600 mg, fed and fasted states) and for up to 3 days as an oral dispersion (200-800 mg day(-1)). Plasma concentrations of OZ439 and its metabolites were measured by LC-MS.
  
  
  RESULTS
  The pharmacokinetic (PK) profile of OZ439 was characterized by a t(max) of around 3 h, followed by a multiphasic profile with a terminal half-life of 25-30 h. The PK parameters were approximately dose proportional for each group and profiles of the metabolites followed a similar pattern to that of the parent compound. Following dosing for 3 days, accumulation was less than two-fold but steady-state was not achieved. In the presence of food, no effect was observed on the t(1/2) of OZ439 while the exposure was increased by 3 to 4.5-fold. Exposure was higher and inter-subject variability was reduced when OZ439 was administered as an oral dispersion compared with a capsule. The urinary clearance of OZ439 and its metabolites was found to be negligible and OZ439 did not induce CYP3A4. The antimalarial activity profiles of a subset of serum samples suggested that the major antimalarial activity originated from OZ439 rather than from any of the metabolites.
  
  
  CONCLUSIONS
  The safety and pharmacokinetic profile of OZ439 merits progression to phase 2a proof of concept studies in the target population of acute uncomplicated malaria.
authors: Medicines for Malaria Venture, Geneva, Switzerland. moehrlej@mmv.org
authors: Joerg J
authors: JJ
authors: Moehrle
authors: Stephan
authors: S
authors: Duparc
authors: Christoph
authors: C
authors: Siethoff
authors: Paul L M
authors: PL
authors: van Giersbergen
authors: J Carl
authors: JC
authors: Craft
authors: Sarah
authors: S
authors: Arbe-Barnes
authors: Susan A
authors: SA
authors: Charman
authors: Maria
authors: M
authors: Gutierrez
authors: Sergio
authors: S
authors: Wittlin
authors: Jonathan L
authors: JL
authors: Vennerstrom
mesh_terms: D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005215:Fasting; D005260:Female; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010545:Peroxides / Q000009:adverse effects* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000962:Antimalarials; D010545:Peroxides; D000218:Adamantane; C558165:artefenomel