Assessment of Interspecies Differences in Drug-Induced QTc Interval Prolongation in Cynomolgus Monkeys, Dogs and Humans

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• 作者：V. F. S. Dubois ; W. E. A. de Witte ; S. A. G. Visser ; M. Danhof…
• 关键词：cardiovascular safety ; drug development ; interspecies differences ; PKPD modelling ; QT interval prolongation
• 刊名：Pharmaceutical Research
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：33
• 期：1
• 页码：40-51
• 全文大小：1,938 KB
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• 作者单位：V. F. S. Dubois (1)
  W. E. A. de Witte (1)
  S. A. G. Visser (2)
  M. Danhof (1)
  O. Della Pasqua (1) (3) (4)
  on behalf of the Cardiovascular Safety Project Team
  TI Pharma PKPD Platform
  
  1. Leiden Academic Centre for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands
  2. Global DMPK, AstraZeneca R&D, Sodertalje, Sweden
  3. Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, Uxbridge, UK
  4. Clinical Pharmacology & Therapeutics, University College London, London, UK
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Pharmacology and Toxicology
  Pharmacy
  Biochemistry
  Medical Law
  Biomedical Engineering
  
• 出版者：Springer Netherlands
• ISSN：1573-904X

文摘

Background and Purpose The selection of the most suitable animal species and subsequent translation of the concentration-effect relationship to humans are critical steps for accurate assessment of the pro-arrhythmic risk of candidate molecules. The objective of this investigation was to assess quantitatively the differences in the QTc prolonging effects of moxifloxacin between cynomolgus monkeys, dogs and humans. The impact of interspecies differences is also illustrated for a new candidate molecule.