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

• Published in: British journal of clinical pharmacology 2015-10, Vol.80 (4), p.706-715
• Main Authors: Darpo, Borje, Ferber, Georg, Siegl, Peter, Laurijssens, Bart, Macintyre, Fiona, Toovey, Stephen, Duparc, Stephan
• Format: Article
• Language: English
• Subjects: Adamantane - administration & dosage; Adamantane - adverse effects; Adamantane - analogs & derivatives; Adamantane - blood; Adamantane - pharmacokinetics; Adolescent; Adult; Antimalarials - administration & dosage; Antimalarials - adverse effects; Antimalarials - blood; Antimalarials - pharmacokinetics; Clinical Trials; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; exposure–response; Female; Healthy Volunteers; Heart Rate - drug effects; Humans; Long QT Syndrome - chemically induced; malaria; Male; Medicin och hälsovetenskap; Middle Aged; OZ439; Peroxides - administration & dosage; Peroxides - adverse effects; Peroxides - blood; Peroxides - pharmacokinetics; piperaquine; QTc; Quinolines - administration & dosage; Quinolines - adverse effects; Quinolines - blood; Quinolines - pharmacokinetics; Young Adult
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.12680

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 QTcF (ΔΔQTcF) 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 QTcF 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.