title: Translational pharmacokinetic-pharmacodynamic modeling of QTc effects in dog and human.
abstract: BACKGROUND
  Preclinical assessment of the heart rate corrected QT interval (QTc) is an important component of the cardiovascular safety evaluation in drug discovery. Here we aimed to quantify the translational relationship between QTc prolongation and shortening in the conscious telemetered dog and humans by a retrospective pharmacokinetic-pharmacodynamic (PKPD) analysis.
  
  
  METHODS
  QTc effects of 2 proprietary compounds and 2 reference drugs (moxifloxacin and dofetilide) were quantified in conscious dogs and healthy volunteers via a linear and Emax pharmacokinetic-pharmacodynamic models. The translational relationship was quantified by correlating the QTc response from dog and human at matching free drug concentrations.
  
  
  RESULTS
  A consistent translational relationship was found at low delta-QTc intervals indicating that a QTc change of 2.5-8 ms in dog would correspond to a 10 ms change in human.
  
  
  CONCLUSIONS
  The translational relationship developed here can be used to predict the QTc liability in human using preclinical dog data. It could therefore help protect the health of human volunteers, for example by appropriate clinical study design and dose selection, as well as improve future decision-making and help reduce compound attrition due to changes in QT interval.
authors.affiliation: AstraZeneca R&D, Safety Pharmacology, Alderley Park, UK; AstraZeneca R&D, Computational Toxicology, Safety Assessment, Mölndal, Sweden. Electronic address: Joanna.Parkinson@astrazeneca.com.
authors.forename: Joanna
authors.initials: J
authors.lastname: Parkinson
authors.forename: Sandra A G
authors.initials: SA
authors.lastname: Visser
authors.forename: Philip
authors.initials: P
authors.lastname: Jarvis
authors.forename: Chris
authors.initials: C
authors.lastname: Pollard
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Valentin
authors.forename: James W T
authors.initials: JW
authors.lastname: Yates
authors.forename: Lorna
authors.initials: L
authors.lastname: Ewart
mesh_terms: D000328:Adult; D000818:Animals; D001372:Aza Compounds / Q000493:pharmacokinetics* / Q000633:toxicity; D053961:Azabicyclo Compounds / Q000493:pharmacokinetics / Q000633:toxicity; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000633:toxicity; D002219:Carbamates / Q000493:pharmacokinetics / Q000633:toxicity; D017321:Clinical Trials, Phase I as Topic; D004285:Dogs; D004311:Double-Blind Method; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000077266:Moxifloxacin; D010627:Phenethylamines / Q000493:pharmacokinetics* / Q000633:toxicity; D011804:Quinolines / Q000493:pharmacokinetics* / Q000633:toxicity; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D013045:Species Specificity; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000633:toxicity; D013686:Telemetry; D057170:Translational Research, Biomedical; D055815:Young Adult
chemical_list: C574562:AZD1386; D001372:Aza Compounds; D053961:Azabicyclo Compounds; D001562:Benzimidazoles; D002219:Carbamates; D024841:Fluoroquinolones; D010627:Phenethylamines; D011804:Quinolines; D013449:Sulfonamides; C550721:tert-butyl (2-(7-(2-(4-cyano-2-fluorophenoxy)ethyl)-9-oxa-3,7-diazabicyclo(3.3.1)non3-yl)ethyl)carbamate; C063533:dofetilide; D000077266:Moxifloxacin
keywords: Dofetilide; Dog; Methods; Moxifloxacin; PKPD; QT interval; Translation