title: How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines?
abstract: Given that cardiovascular safety liabilities remain a major cause of drug attrition during preclinical and clinical development, adverse drug reactions, and post-approval withdrawal of medicines, the Medical Research Council Centre for Drug Safety Science hosted a workshop to discuss current challenges in determining, understanding and addressing 'Cardiovascular Toxicity of Medicines'. This article summarizes the key discussions from the workshop that aimed to address three major questions: (i) what are the key cardiovascular safety liabilities in drug discovery, drug development and clinical practice? (ii) how good are preclinical and clinical strategies for detecting cardiovascular liabilities? and (iii) do we have a mechanistic understanding of these liabilities? It was concluded that in order to understand, address and ultimately reduce cardiovascular safety liabilities of new therapeutic agents there is an urgent need to: • Fully characterize the incidence, prevalence and impact of drug-induced cardiovascular issues at all stages of the drug development process. • Ascertain the predictive value of existing non-clinical models and assays towards the clinical outcome. • Understand the mechanistic basis of cardiovascular liabilities; by addressing areas where it is currently not possible to predict clinical outcome based on preclinical safety data. • Provide scientists in all disciplines with additional skills to enable them to better integrate preclinical and clinical data and to better understand the biological and clinical significance of observed changes. • Develop more appropriate, highly relevant and predictive tools and assays to identify and wherever feasible to eliminate cardiovascular safety liabilities from molecules and wherever appropriate to develop clinically relevant and reliable safety biomarkers.
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, The University of Liverpool, Merseyside, UK.
authors.forename: Hg
authors.initials: H
authors.lastname: Laverty
authors.forename: C
authors.initials: C
authors.lastname: Benson
authors.forename: Ej
authors.initials: E
authors.lastname: Cartwright
authors.forename: Mj
authors.initials: M
authors.lastname: Cross
authors.forename: C
authors.initials: C
authors.lastname: Garland
authors.forename: T
authors.initials: T
authors.lastname: Hammond
authors.forename: C
authors.initials: C
authors.lastname: Holloway
authors.forename: N
authors.initials: N
authors.lastname: McMahon
authors.forename: J
authors.initials: J
authors.lastname: Milligan
authors.forename: Bk
authors.initials: B
authors.lastname: Park
authors.forename: M
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: C
authors.initials: C
authors.lastname: Pollard
authors.forename: J
authors.initials: J
authors.lastname: Radford
authors.forename: N
authors.initials: N
authors.lastname: Roome
authors.forename: P
authors.initials: P
authors.lastname: Sager
authors.forename: S
authors.initials: S
authors.lastname: Singh
authors.forename: T
authors.initials: T
authors.lastname: Suter
authors.forename: W
authors.initials: W
authors.lastname: Suter
authors.forename: A
authors.initials: A
authors.lastname: Trafford
authors.forename: Pga
authors.initials: P
authors.lastname: Volders
authors.forename: R
authors.initials: R
authors.lastname: Wallis
authors.forename: R
authors.initials: R
authors.lastname: Weaver
authors.forename: M
authors.initials: M
authors.lastname: York
authors.forename: Jp
authors.initials: J
authors.lastname: Valentin
mesh_terms: D000818:Animals; D002317:Cardiovascular Agents / Q000009:adverse effects*; D002319:Cardiovascular System / Q000187:drug effects*; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans
chemical_list: D002317:Cardiovascular Agents