First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials

AIMS: To asses 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) for up to 3 days as an oral dispersion (200-800 mg/day). Plasma concentrations of OZ439 and its metabolites were measured by LC-MS. RESULTS: The pharmacokinetic (PK) profile of OZ439 was characterised by a t(max) of around 3 hours, followed by multiphasic profile with a terminal half-life of 25-30 hours. 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 2-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 to 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. CONCLUSION: The safety and pharmacokinetic profile of OZ439 merits progression to Phase 2a proof-of concept studies in the target population of acute uncomplicated malaria