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

Abstract

Aims: 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.

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.

© 2012 Medicines for Malaria Venture (MMV). British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Figures

Figure 1

Structure of OZ439 and its potential metabolites

Figure 2

Arithmetic mean plasma concentration vs. time profiles of OZ439 in healthy subjects after administration of (A) a single dose (n = 6–8 per group) of 50, 100, 200, 400, 800 or 1200 mg (capsule) under fasted conditions, (B) a single dose (n = 5–6 per group) of 400, 800 or 1600 mg (oral dispersion) under fasted conditions, (C) a single dose (n = 12 per group) of 800 mg (oral dispersion) under fasted and fed conditions and (D) multiple doses (n = 6 per group) of 200, 400 or 800 mg (oral dispersion) once a day for 3 days under fasted conditions. Error bars represent SDs. (A) •, 50 mg; ▿, 100 mg; ▪, 200 mg; ◊, 400 mg; ▴, 800 mg; ○, 1200 mg; (B) •, 400 mg; ▿, 800 mg; ▪, 1800 mg; (C) •, fasted; ▿, fed; (D) •, 200 mg; ▿, 400 mg; ▪, 800 mg

Figure 3

Individual dose normalized values for OZ439 AUC after administration of (A) single doses of 50, 100, 200, 400, 800 or 1200 mg (capsule), (B) single doses of 400, 800 or 1600 mg (oral dispersion) and (C) multiple doses of 200, 400 or 800 mg once daily for 3 days (oral dispersion) to healthy subjects (n = 5–8 per group). Horizontal lines represent the geometric mean for each dose group