First‐in‐man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials. (10th January 2013)

• Record Type: Journal Article
• Authors: Moehrle, Joerg J.; Duparc, Stephan; Siethoff, Christoph; van, Paul L. M.; Craft, J. Carl; Arbe‐Barnes, Sarah; Charman, Susan A.; Gutierrez, Maria; Wittlin, Sergio; Vennerstrom, Jonathan L.
• Is Part Of: British journal of clinical pharmacology. Volume 75:Number 2(2013:Feb.)
• Page Start: 535
• Page End: 548
• Publication Date: 2013-01-10
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/j.1365-2125.2012.04368.x
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp4368-sec-0001" sec-type="section"> <title>Aims</title> <p>To assess the safety and pharmacokinetics of a new synthetic ozonide antimalarial, OZ439, in a first‐in‐man, double‐blind study in healthy volunteers.</p> </sec> <sec id="bcp4368-sec-0002" sec-type="section"> <title>Methods</title> <p>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<sup>−1</sup>). Plasma concentrations of OZ439 and its metabolites were measured by LC‐MS.</p> </sec> <sec id="bcp4368-sec-0003" sec-type="section"> <title>Results</title> <p>The pharmacokinetic (PK) profile of OZ439 was characterized by a <italic>t</italic><sub>max</sub> 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 <italic>t</italic><sub>1/2</sub> 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.</p> </sec> <sec id="bcp4368-sec-0004" sec-type="section"> <title>Conclusion</title> <p>The safety and pharmacokinetic profile of OZ439 merits progression to phase 2a proof of concept studies in the target population of acute uncomplicated malaria.</p> </sec> </abstract>