title: 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: OBJECTIVE
  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.affiliation: Associate Professor of Cardiology, Karolinska Institute, Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd's Hospital, Stockholm, Sweden.
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
authors.affiliation: Georg Ferber Statistical Consultant, Riehen, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Ferber
authors.affiliation: Siegl Pharma Consulting LLC, Blue Bell, Pennsylvania, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Siegl
authors.affiliation: BEL Pharm Consulting, Chambonas, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Laurijssens
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Fiona
authors.initials: F
authors.lastname: Macintyre
authors.affiliation: Pegasus Research, London, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Toovey
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Duparc
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D010545:Peroxides / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult; D010879:Piperazines
chemical_list: D000218:Adamantane; D000962:Antimalarials; D010545:Peroxides; D011804:Quinolines; C034759:piperaquine; D010879:Piperazines; C558165:artefenomel
keywords: OZ439; QT; QTc; exposure-response; malaria; piperaquine