1. A tutorial on model informed approaches to cardiovascular safety with focus on cardiac repolarisation
- Author
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Å. M. Kragh, T. Vik, Teresa Collins, Chris Pollard, Joanna Parkinson, Cecilia Arfvidsson, Corina Dota, S. Y. A. Cheung, Bengt Hamrén, Helen Tomkinson, U. Wählby-Hamrén, and Linnéa Bergenholm
- Subjects
Drug-Related Side Effects and Adverse Reactions ,Computer science ,Guinea Pigs ,Pharmacology toxicology ,Drug Evaluation, Preclinical ,Blood Pressure ,030204 cardiovascular system & hematology ,Cardiovascular System ,030226 pharmacology & pharmacy ,03 medical and health sciences ,Dogs ,0302 clinical medicine ,Heart Rate ,Drug Discovery ,Animals ,Humans ,Hemodynamic effects ,Pharmacology ,Cardiovascular safety ,Project strategy ,Macaca mulatta ,Rats ,Focus (linguistics) ,Pharmaceutical Preparations ,Drug development ,Risk analysis (engineering) ,Cardiovascular Diseases ,Cardiotoxicities ,Rabbits - Abstract
Drugs can affect the cardiovascular (CV) system either as an intended treatment or as an unwanted side effect. In both cases, drug-induced cardiotoxicities such as arrhythmia and unfavourable hemodynamic effects can occur, and be described using mathematical models; such a model informed approach can provide valuable information during drug development and can aid decision-making. However, in order to develop informative models, it is vital to understand CV physiology. The aims of this tutorial are to present (1) key background biological and medical aspects of the CV system, (2) CV electrophysiology, (3) CV safety concepts, (4) practical aspects of development of CV models and (5) regulatory expectations with a focus on using model informed and quantitative approaches to support nonclinical and clinical drug development. In addition, we share several case studies to provide practical information on project strategy (planning, key questions, assumptions setting, and experimental design) and mathematical models development that support decision-making during drug discovery and development.
- Published
- 2018