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