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Br J Clin Pharmacol. 2015 Oct;80(4):706-15. doi: 10.1111/bcp.12680. Epub 2015 Jul 14.

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

Author information

1
Associate Professor of Cardiology, Karolinska Institute, Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd's Hospital, Stockholm, Sweden.
2
Georg Ferber Statistical Consultant, Riehen, Switzerland.
3
Siegl Pharma Consulting LLC, Blue Bell, Pennsylvania, USA.
4
BEL Pharm Consulting, Chambonas, France.
5
Medicines for Malaria Venture, Geneva, Switzerland.
6
Pegasus Research, London, UK.

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.

KEYWORDS:

OZ439; QT; QTc; exposure-response; malaria; piperaquine

PMID:
25966781
PMCID:
PMC4594707
DOI:
10.1111/bcp.12680
[Indexed for MEDLINE]
Free PMC Article

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