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

13 May 2015

Borje Darpo, Georg Ferber, Peter Siegl, Bart Laurijssens, Fiona Macintyre, Stephen Toovey, Stephen Duparc

British Journal of Clinical Pharmacology

DOI: 10.1111/bcp.12680

Abstract

AIMS:

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. 12-lead ECG tracings and PK samples were collected serially pre- and post-dosing.

RESULTS:

A significant relation between plasma levels and placebo-corrected change-from-baseline QTcF (∆∆QTcF) was demonstrated for piperaquine, but not for OZ439, with a mean slope of 0.047 ms per ng/mL (90% CI: 0.038 to 0.057). Using an ER model that accounts for plasma concentrations of both piperaquine and OZ439, a largest mean QTcF effect of 14 ms (90% CI: 10 to 18 ms) and 18 ms (14 to 22 ms) was predicted at expected plasma levels of a single- dose 800 mg OZ439 combined with PQP 960 mg (188 ng/mL) and 1440 mg (281 ng/mL), 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 levels compared to available 3-day PQP - artemisinin combinations and can therefore be predicted to cause less QTc prolongation. This article is protected by copyright. All rights reserved.

Read the full article on the Wiley online library.