How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines?

被引：276

作者：

Laverty, H. G. ^{[1
]}

Benson, C. ^{[2
]}

Cartwright, E. J. ^{[3
]}

Cross, M. J. ^{[1
]}

Garland, C. ^{[4
]}

Hammond, T. ^{[5
]}

Holloway, C. ^{[6
]}

McMahon, N. ^{[7
]}

Milligan, J. ^{[5
]}

Park, B. K. ^{[1
]}

Pirmohamed, M. ^{[1
]}

Pollard, C. ^{[5
]}

Radford, J. ^{[8
]}

Roome, N. ^{[9
]}

Sager, P. ^{[10
]}

Singh, S. ^{[11
]}

Suter, T. ^{[12
]}

Suter, W. ^{[13
]}

Trafford, A. ^{[14
]}

Volders, P. G. A. ^{[15
]}

Wallis, R. ^{[16
]}

Weaver, R. ^{[17
]}

York, M. ^{[7
]}

Valentin, J. P. ^{[5
]}

机构：

[1] Univ Liverpool, MRC Ctr Drug Safety Sci, Dept Mol & Clin Pharmacol, Liverpool L69 3GE, Merseyside, England

[2] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA

[3] Univ Manchester, Manchester Acad Hlth Sci Ctr, Sch Biomed, Manchester, Lancs, England

[4] Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England

[5] AstraZeneca, Safety Assessment UK, Macclesfield, Cheshire, England

[6] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England

[7] GlaxoSmithKline, Safety Assessment, Ware, Herts, England

[8] Christie NHS Fdn Trust, Manchester, Lancs, England

[9] Sanofi Aventis, Disposit Safety & Anim Res, Porcheville Site, France

[10] Cardiac Safety Res Consortium Sci Oversight Comm, Sager Consulting Partners & Chair, San Francisco, CA USA

[11] Med & Healthcare Prod Regulatory Agcy UK, Cardiovasc Therapeut Area, London, England

[12] Univ Hosp Bern, Swiss Cardiovasc Ctr, Inselspital, CH-3010 Bern, Switzerland

[13] Novartis Pharma AG, Novartis Inst BioMed Res, Translat Sci TS, PCS GeneSafe,CHMZ, Muttenz, Switzerland

[14] Univ Manchester, Core Technol Facil, Manchester, Lancs, England

[15] Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Cardiol, Med Ctr, Maastricht, Netherlands

[16] Pfizer, Drug Safety Res & Dev, Groton, CT USA

[17] Servier Res & Dev Ltd, Ctr Biopharm Res, Slough, Berks, England

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2011年 / 163卷 / 04期

关键词：

cardiovascular safety liabilities; medicines; adverse drug reaction; adverse event; patient safety; drug attrition; QT INTERVAL PROLONGATION; TORSADES-DE-POINTES; BLOOD-PRESSURE; DRUG; HEART; MECHANISMS; TOXICITY; HUMANS; ELECTROPHYSIOLOGY; RECOMMENDATIONS;

D O I：

10.1111/j.1476-5381.2011.01255.x

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：675 / 693

页数：19

共 75 条

[1] Ligand structural aspects of hERG channel blockade [J].

Aronov, Alex M. .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2008, 8 (13) :1113-1127

[2] International life sciences institute (health and environmental sciences institute, HESI) initiative on moving towards better predictors of drug-induced torsades de pointes [J].

Bass, A. S. ;

Darpo, B. ;

Breidenbach, A. ;

Bruse, K. ;

Feldman, H. S. ;

Garnes, D. ;

Hammond, T. ;

Haverkamp, W. ;

January, C. ;

Koerner, J. ;

Lawrence, C. ;

Leishman, D. ;

Roden, D. ;

Valentin, J. P. ;

Vos, M. A. ;

Zhou, Y-Y ;

Karluss, T. ;

Sager, P. .

BRITISH JOURNAL OF PHARMACOLOGY, 2008, 154 (07) :1491-1501

[3]

Bass Alan, 2007, Journal of Pharmacological and Toxicological Methods, V56, P91, DOI 10.1016/j.vascn.2007.05.001

[4]

BAUBUIN L, 2005, CMAJ, V173, P1191

[5] Cardiac lesions induced by neuroleptic drugs in the rabbit [J].

Belhani, D ;

Frassati, D ;

Mégard, R ;

Tsibiribi, P ;

Bui-Xuan, B ;

Tabib, A ;

Fanton, L ;

Malicier, D ;

Descotes, J ;

Timour, Q .

EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY, 2006, 57 (03) :207-212

[6] Cardiac excitation-contraction coupling [J].

Bers, DM .

NATURE, 2002, 415 (6868) :198-205

[7] Cardiovascular safety of drugs not intended for cardiovascular use: need for a new conceptual basis for assessment and approval [J].

Borer, Jeffrey S. ;

Pouleur, Hubert ;

Abadie, Eric ;

Follath, Ferrenc ;

Wittes, Janet ;

Pfeffer, Marc A. ;

Pitt, Bertram ;

Zannad, Faiez .

EUROPEAN HEART JOURNAL, 2007, 28 (15) :1904-1909

[8]

Brott D. A., 2005, Cancer Biomarkers, V1, P15

[9] National surveillance of emergency department visits for outpatient adverse drug events [J].

Budnitz, Daniel S. ;

Pollock, Daniel A. ;

Weidenbach, Kelly N. ;

Mendelsohn, Aaron B. ;

Schroeder, Thomas J. ;

Annest, Joseph L. .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2006, 296 (15) :1858-1866

[10]

CARB B, 2006, AM DRUG DISCOV, V1, P53

← 1 2 3 4 5 6 7 8 →