Parkinson_2013_CardiacSafety_Dog_Translational

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Model comprised of files: Executable_run6.ctl, Simulated_dog_PKPD.txt, Output_simulated_run6.lst, Command.txt
Original code
  • Translational pharmacokinetic-pharmacodynamic modeling of QTc effects in dog and human.
  • Parkinson J1, Visser SA, Jarvis P, Pollard C, Valentin JP, Yates JW, Ewart L.
  • J Pharmacol Toxicol Methods, 12/2013, Volume 68, Issue 3, pages: 357-66
  • 1AstraZeneca R&D, Safety Pharmacology, Alderley Park, UK; AstraZeneca R&D, Computational Toxicology, Safety Assessment, Mölndal, Sweden. Electronic address: Joanna.Parkinson@astrazeneca.com.
  • INTRODUCTION: 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. DISCUSSION: 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.
Amy Cheung
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  • Model owner: Amy Cheung
  • Submitted: Dec 11, 2015 12:38:48 PM
  • Last Modified: Dec 11, 2015 12:38:48 PM
Revisions
  • Version: 9 public model Download this version
    • Submitted on: Dec 11, 2015 12:38:48 PM
    • Submitted by: Amy Cheung
    • With comment: Edited model metadata online.
 
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