title: Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase.
abstract: The QT effects of five "QT-positive" and one negative drug were tested to evaluate whether exposure-response analysis can detect QT effects in a small study with healthy subjects. Each drug was given to nine subjects (six for placebo) in two dose levels; positive drugs were chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation. The slope of the concentration/ΔQTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. For the lower dose, an effect above 10 ms could not be excluded, i.e., the upper bound of the confidence interval for the predicted mean ΔΔQTcF effect was above 10 ms. For the negative drug, levocetirizine, a ΔΔQTcF effect above 10 ms was excluded at 6-fold the therapeutic dose. The study provides evidence that robust QT assessment in early-phase clinical studies can replace the thorough QT study.
authors: Karolinska Institutet, Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd's Hospital, Stockholm, Sweden; iCardiac Technologies, Rochester, New York, USA.
authors: B
authors: B
authors: Darpo
authors: C
authors: C
authors: Benson
authors: C
authors: C
authors: Dota
authors: G
authors: G
authors: Ferber
authors: C
authors: C
authors: Garnett
authors: C L
authors: CL
authors: Green
authors: V
authors: V
authors: Jarugula
authors: L
authors: L
authors: Johannesen
authors: J
authors: J
authors: Keirns
authors: K
authors: K
authors: Krudys
authors: J
authors: J
authors: Liu
authors: C
authors: C
authors: Ortemann-Renon
authors: S
authors: S
authors: Riley
authors: N
authors: N
authors: Sarapa
authors: B
authors: B
authors: Smith
authors: R R
authors: RR
authors: Stoltz
authors: M
authors: M
authors: Zhou
authors: N
authors: N
authors: Stockbridge
mesh_terms: D000328:Adult; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D016014:Linear Models; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D011446:Prospective Studies
chemical_list: D002317:Cardiovascular Agents