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A tutorial on model informed approaches to cardiovascular safety with focus on cardiac repolarisation

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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.

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Diagram adapted from Sallam et al. [71]

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Acknowledgements

The authors thank David Carlile, Solange Corriol-Rohou, Amy Pointon, Dinko Rekic and James Yates for review and discussion of the article and Fig. 4 was provided by David Svensson. The author would like to thank Don Stanski, Ulf Eriksson, James Li, Nidal Al-Huniti, James Yates, Craig Lambert, Jay Mettetal, Charlotte Kroft, Zinnia Parra-Guillen, Niklas Hartung, Wendy Aartsen, Thomas Leja, Mats O. Karlsson, Liesbeth Lange, Lena Friberg, Paolo Magni, Mike Smith, Lutz Harnisch and Peter Milligan for their supports and discussions in the organisation of AstraZeneca lead IMI DDMoRe (Drug Diseases Model Resources) Cardiac Safety course. Work performed by S. Y. Amy Cheung, Joanna Parkinson, Ulrika Wählby-Hamrén, Corina D. Dota, Åsa Kragh, Torbjörn Vik, Teresa Collins, Cecilia Arfvidsson, Chris E. Pollard, Helen K. Tomkinson and Bengt Hamrén are funded by AstraZeneca. Work performed by Linnea Bergenholm was supported through the Marie Curie FP7 ITN EID project No. 316736, IMPACT “Innovative Modeling for Pharmacological Advances through Collaborative Training” and through the NC3Rs/EPSRC project No. NC/K001205/1 “Structural Identifiability and Indistinguishability Analysis as Tools for Quantitative and Systems Pharmacology to Support the 3Rs.” Part of the manuscript is written based on materials from the AstraZeneca lead IMI DDMoRe Cardiac Safety course with input from Freie Universitaet Berlin where both AstraZeneca and Freie Universitaet Berlin are IMI DDMoRe consortium partners. Innovative Medicines Initiative (IMI) Joint Undertaking under grant Agreement No. 115156, resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (FP7/2007–2013) and European Federation of Pharmaceutical Industries and Association’s companies in kind contribution. The DDMoRe project is also financially supported by contributions from academia and small and medium enterprise partners (SME).

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Authors and Affiliations

  1. Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Cambridge, UK

    S. Y. A. Cheung & H. K. Tomkinson

  2. Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden

    J. Parkinson, U. Wählby-Hamrén, C. D. Dota, Å. M. Kragh & B. Hamrén

  3. Cardiovascular Safety Center of Excellence, Global Medicine Development, Gothenburg, Sweden

    T. Vik

  4. DMPK CVRM Modelling and Simulation, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden

    L. Bergenholm

  5. Safety and ADME Translational Sciences Department, Drug Safety and Metabolism, IMED Biotech Unit, Cambridge, UK

    T. Collins & C. E. Pollard

  6. Clinical Operation, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden

    C. Arfvidsson

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Correspondence to S. Y. A. Cheung.

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S.Y.A.C., J.P., U.W.-H., C.D.D., Å.M.K., T.V., T.C., L.B., C.A., C.E.P., H.K.T. and B.H. are employees of AstraZeneca Pharmaceuticals.

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Cheung, S.Y.A., Parkinson, J., Wählby-Hamrén, U. et al. A tutorial on model informed approaches to cardiovascular safety with focus on cardiac repolarisation. J Pharmacokinet Pharmacodyn 45, 365–381 (2018). https://doi.org/10.1007/s10928-018-9589-6

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  • DOI: https://doi.org/10.1007/s10928-018-9589-6

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