Evaluation of the QT effect of a combination of piperaquine and a novel anti-malarial drug candidate OZ439, for the treatment of uncomplicated malaria.

Abstract

AIMS:

The aim was to investigate the QT effect of a single dose combination regimen of piperaquine phosphate (PQP) and a novel aromatic trioxolane, OZ439, for malaria treatment.

METHODS:

Exposure-response (ER) analysis was performed on data from a placebo-controlled, single dose, study with OZ439 and PQP. Fifty-nine healthy subjects aged 18 to 55 years received OZ439 alone or placebo in a first period, followed by OZ439 plus PQP or matching placebos in period 2. OZ439 and PQP doses ranged from 100-800 mg and 160-1440 mg, respectively. Twelve-lead ECG tracings and PK samples were collected serially pre- and post-dosing.

RESULTS:

A significant relation between plasma concentrations and placebo-corrected change from baseline QTc F (ΔΔQTc F) was demonstrated for piperaquine, but not for OZ439, with a mean slope of 0.047 ms per ng ml(-1) (90% CI 0.038, 0.057). Using an ER model that accounts for plasma concentrations of both piperaquine and OZ439, a largest mean QTc F effect of 14 ms (90% CI 10, 18 ms) and 18 ms (90% CI 14, 22 ms) was predicted at expected plasma concentrations of a single dose 800 mg OZ439 combined with PQP 960 mg (188 ng ml(-1) ) and 1440 mg (281 ng ml(-1) ), respectively, administered in the fasted state.

CONCLUSIONS:

Piperaquine prolongs the QTc interval in a concentration-dependent way. A single dose regimen combining 800 mg OZ439 with 960 mg or 1440 mg PQP is expected to result in lower peak piperaquine plasma concentrations compared with available 3 day PQP-artemisinin combinations and can therefore be predicted to cause less QTc prolongation.

• Authors: Borje Darpo, Georg Ferber, Peter Siegl, Bart Laurijssens, Fiona Macintyre, Stephen Toovey, Stephan Duparc
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 80 Issue 4 Pg. 706-15 (Oct 2015) ISSN: 1365-2125 [Electronic] England
• PMID: 25966781 (Publication Type: Journal Article, Randomized Controlled Trial)
• Copyright: © 2015 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

Chemical References

• Antimalarials
• Peroxides
• Quinolines
• piperaquine
• Adamantane
• artefenomel

Topics

• Adamantane (administration & dosage, adverse effects, analogs & derivatives, blood, pharmacokinetics)
• Adolescent
• Adult
• Antimalarials (administration & dosage, adverse effects, blood, pharmacokinetics)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Interactions
• Drug Therapy, Combination
• Female
• Healthy Volunteers
• Heart Rate (drug effects)
• Humans
• Long QT Syndrome (chemically induced)
• Male
• Middle Aged
• Peroxides (administration & dosage, adverse effects, blood, pharmacokinetics)
• Quinolines (administration & dosage, adverse effects, blood, pharmacokinetics)
• Young Adult