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Project 4 - Modelling Cardiovascular Safety - Target Engagement Exposure

ESR - Linnea Bergenholm

Aims

The project focuses on cardiovascular safety in drug discovery and development. A number of cardiovascular biomarkers are analysed pre-clinically to guide for example compound selection and dose selection for first in human studies. My goal is to increase our knowledge of how well biomarkers for drug-induced effects on cardiac conduction in humans translate from pre-clinical studies. This may potentially reduce drug attrition as well as increase patient safety.

I use quantitative systems pharmacology methods to predict and translate cardiovascular effects between in vitro bioassays, in vivo animal studies and the clinic. This work entails quantification of the concentration-effect relationships in pre-clinical species and humans through pharmacokinetic/pharmacodynamic modelling and analysis of the translation between species. Compartmental models are used to describe drug disposition, providing a model describing the plasma drug concentration over time. Algebraic or mechanism-based models are then used to relate the drug concentration to the pharmacodynamic effect.

Supervisors: Joanna Parkinson (AstraZeneca).

Co-Supervisors: Teresa Collins (AstraZeneca), Neil Evans (University of Warwick), Mike Chappell (University of Warwick).

Project Objectives
  • To quantify the exposure-effect relationship for individual cardiovascular parameters in preclinical species and man for reference agents with different mechanisms-of-action.
  • Develop a translational systems pharmacology framework to describe, explain and predict the cardiovascular (side) effects in preclinical and clinical species by separating drug and system-specific parameters.
  • Incorporate the mechanism-of-action (in vitro observations of multichannel inhibition) into translational systems pharmacology models.
  • Define the optimal (maximising confidence in prediction whilst minimising resources) approach to predict cardiovascular (side) effects in man i.e. in vitro vs. multiple species.
Project Update

Currently, I am focusing on the pre-clinical to clinical translation of two biomarkers for drug-induced effects on cardiac conduction, namely the QRS and PR intervals in the electrocardiogram (ECG).

Publications

  • Janzén, D.L.I, Bergenholm, L., Jirstrand, M., Parkinson, J., Yates, J., Evans, N.D., Chappell, M.J. Parameter identifiability of fundamental pharmacodynamic models. Frontiers in Physiology. 7:590, 2016 (doi.org/10.3389/fphys.2016.00590).
  • Bergenholm, L., Collins, T., Evans, N. D., Chappell, M. J., & Parkinson, J. (2016). PKPD modelling of PR and QRS intervals in conscious dogs using standard safety pharmacology data. Journal of Pharmacological and Toxicological Methods, 79, 34–44. (10.1016/j.vascn.2016.01.002).
  • Collins, T. A., Bergenholm, L., Abdulla, T., Yates, J. W. T., Evans, N., Chappell, M. J., & Mettetal, J. T. (2015). Modeling and Simulation Approaches for Cardiovascular Function and Their Role in Safety Assessment. CPT: Pharmacometrics & Systems Pharmacology, 4(March), 1–14. (10.1002/psp4.18).

Conference Papers

  • 7th September 2016: ‘Nonclinical to clinical translation of biomarkers for drug-induced effects on cardiac conduction’. Quantitative Systems Pharmacology-UK (QSP-UK), University of Surrey, UK.
  • 22nd April 2016: School of Engineering postgraduate symposium, University of Warwick, Coventry, UK. Quantifying drug-induced changes in cardiac conduction in vivo.

Poster Presentations

  • 17th August 2016: Uppsala Pharmacometric Summer School, Uppsala, Sweden.
  • 18th-20th November 2015: Pharmacokinetics UK (PKUK), Chester, United Kingdom. Poster presentation entitled ‘Population PKPD modelling of QRS and PR intervals in conscious dogs.
  • 2nd-5th June 2015: Population Approach Group in Europe (PAGE), Crete, Greece, Poster presentation entitled ‘Population PKPD modelling of QRS and PR intervals in conscious dogs.
  • 9th March 2015: School of Engineering postgraduate symposium, University of Warwick. Poster presentation entitled ‘Dog to human translation of the anti-arrhythmic drug flecainide’
  • 17th-19th December 2014: Modelling and Simulation Symposium AstraZeneca. Poster Presentation entitled ‘Translation of pre-clinical cardiovascular biomarkers to clinical ECG effects for the anti-arrhythmic drug flecainide’
  • 5th-7th November 2014: Pharmacokinetics UK (PKUK), Bath, United Kingdom. Poster Presentation entitled ‘Translation from pre-clinical to clinical effects of a drug that prolongs the QRS complex’
  • 23rd-25th April 2014: 7th Noordwijkerhout Symposium on Pharmacokinetics, Pharmacodynamics and Systems Pharmacology, Systems Pharmacology in Drug Discovery & Development in Noordwijkerhout, The Netherlands. Poster presentation entitled ‘Translating pre-clinical cardiovascular biomarkers to clinical effects: Preliminary results for a drug that prolongs the QRS complex’
  • 3rd-4th December 2013: Modelling and Simulation Symposium AstraZeneca Alderley Park, UK. Poster Presentation entitled ‘Assessing cardiovascular safety beyond QT: Translational PK/PD modelling of cardiovascular parameters to improve safety and efficiency in drug development’.
  • 14th-15th November 2013: British Society of Toxicological Pathology / Safety Pharmacology Society meeting on cardiovascular risk assessment at AstraZeneca, Sweden. Poster presentation entitled ‘Assessing cardiovascular safety beyond QT: Translational PK/PD modelling of cardiovascular parameters to improve safety and efficiency in drug development’.
  • 30th October - 1st November 2013: Pharmacokinetics UK (PKUK), Harrogate, United Kingdom. Poster presentation entitled ‘Assessing cardiovascular safety beyond QT: Translational PK/PD modelling of cardiovascular parameters to improve safety and efficiency in drug development’.

Other Presentations

  • Bergenholm, L. Nonclinical to clinical translation of biomarkers for drug-induced effects on cardiac conduction. Safety ADME and Translational Sciences (SATS) science forum, Gothenburg, Sweden, May 2016.
  • Bergenholm, L. Translating pre-clinical biomarkers for drug-induced changes in cardiac conduction to effects in humans. Safety ADME and Translational Sciences (SATS) Modelling & Informatics (M&I) team meeting, Gothenburg, Sweden, March 2016.
  • Bergenholm, L. & Janzén, D. Structural identifiability analysis of systems pharmacology models. Safety ADME and Translational Sciences (SATS) Modelling & Informatics (M&I) team meeting, Gothenburg, Sweden, March 2016.
  • Trägårdh, M., Gennemark, P., Bergenholm, L., Janzén, D. Methods in Modelling & Simulation. Project & Science learnings, Gothenburg, Sweden, November 2015.
  • Bergenholm, L. Clinical ECG effects of antiarrhythmic compounds identified in a literature study. Translational Safety (TS) team meeting, Gothenburg, Sweden. September 2015.
  • Bergenholm, L. Flecainide dog modelling and translation using literature data. Presented at: Discovery safety team meeting, Gothenburg, Sweden. December 2014.
  • Bergenholm, L. Modelling for cardiovascular safety: Translating QRS and PR prolongation of AZD1305 from dog to human. Translational Safety (TS) team meeting, Gothenburg, Sweden. November 2014.
  • Bergenholm, L. Modelling for cardiovascular safety: Translating electrophysiological parameters from dog to human. ECG centre, Gothenburg, Sweden for internal education purpose. September 2014.
  • Bergenholm, L. Modelling for cardiovascular safety: Translating electrophysiological parameters from dog to human. IMPACT presentation event, Gothenburg, Sweden. May 2014.


Conferences Attended

  • 18th-20th November 2015: Pharmacokinetics UK (PKUK), Chester, United Kingdom.
  • 2nd-5th June 2015: Population Approach Group in Europe (PAGE), Crete, Greece.
  • 17th-19th December 2014: Modelling and Simulation Symposium AstraZeneca.
  • 5th-7th November 2014: Pharmacokinetics UK (PKUK), Bath, United Kingdom.
  • 23rd-25th April 2014: 7th Noordwijkerhout Symposium on Pharmacokinetics, Pharmacodynamics and Systems Pharmacology, Systems Pharmacology in Drug Discovery & Development in Noordwijkerhout, The Netherlands.
  • 3rd-4th December 2013: Modelling and Simulation Symposium AstraZeneca Alderley Park, UK.
  • 14th-15th November 2013: British Society of Toxicological Pathology / Safety Pharmacology Society meeting on cardiovascular risk assessment at AstraZeneca, Sweden.
  • 30th October - 1st November 2013: Pharmacokinetics UK (PKUK), Harrogate, United Kingdom.

Awards and Impacts

  • February 2017: PhD awarded to Linnea Bergenholm for her thesis entitled ‘Predicting QRS and PR Interval Prolongations in Humans using Nonclinical Data’.