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

Joerg J. Moehrle, Stephan Duparc, Christoph Siethoff, Paul L.M. van Giersbergen, J. Carl Craft, Sarah Arbe-Barnes, Susan A. Charman, Maria Gutierrez, Sergio Wittlin, Jonathan L Vennerstrom

Research output: Contribution to journalArticle

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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 (50-1200mg) or an oral dispersion (400-1600mg, fed and fasted states) and for up to 3 days as an oral dispersion (200-800mg 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 3h, followed by a multiphasic profile with a terminal half-life of 25-30h. 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.

Original languageEnglish (US)
Pages (from-to)535-548
Number of pages14
JournalBritish Journal of Clinical Pharmacology
Volume75
Issue number2
DOIs
StatePublished - Jan 1 2013

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Peroxides
Antimalarials
Pharmacokinetics
Safety
Capsules
Cytochrome P-450 CYP3A
Health Services Needs and Demand
Double-Blind Method
Half-Life
Healthy Volunteers
Food
1,2,4-trioxane
Serum

Keywords

  • Healthy subjects
  • OZ439
  • Phamacokinetics
  • Safety
  • Synthetic ozonide

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials. / Moehrle, Joerg J.; Duparc, Stephan; Siethoff, Christoph; van Giersbergen, Paul L.M.; Craft, J. Carl; Arbe-Barnes, Sarah; Charman, Susan A.; Gutierrez, Maria; Wittlin, Sergio; Vennerstrom, Jonathan L.

In: British Journal of Clinical Pharmacology, Vol. 75, No. 2, 01.01.2013, p. 535-548.

Research output: Contribution to journalArticle

Moehrle, Joerg J. ; Duparc, Stephan ; Siethoff, Christoph ; van Giersbergen, Paul L.M. ; Craft, J. Carl ; Arbe-Barnes, Sarah ; Charman, Susan A. ; Gutierrez, Maria ; Wittlin, Sergio ; Vennerstrom, Jonathan L. / First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials. In: British Journal of Clinical Pharmacology. 2013 ; Vol. 75, No. 2. pp. 535-548.
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AU - Duparc, Stephan

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AU - van Giersbergen, Paul L.M.

AU - Craft, J. Carl

AU - Arbe-Barnes, Sarah

AU - Charman, Susan A.

AU - Gutierrez, Maria

AU - Wittlin, Sergio

AU - Vennerstrom, Jonathan L

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