Physiological, pharmacological and toxicological considerations of drug‐induced structural cardiac injury

Abstract

The incidence of drug-induced structural cardiotoxicity, which may lead to heart failure, has been recognized in association with the use of anthracycline anti-cancer drugs for many years, but has also been shown to occur following treatment with the new generation of targeted anti-cancer agents that inhibit one or more receptor or non-receptor tyrosine kinases, serine/threonine kinases as well as several classes of non-oncology agents. A workshop organized by the Medical Research Council Centre for Drug Safety Science (University of Liverpool) on 5 September 2013 and attended by industry, academia and regulatory representatives, was designed to gain a better understanding of the gaps in the field of structural cardiotoxicity that can be addressed through collaborative efforts. Specific recommendations from the workshop for future collaborative activities included: greater efforts to identify predictive (i) preclinical; and (ii) clinical biomarkers of early cardiovascular injury; (iii) improved understanding of comparative physiology/pathophysiology and the clinical predictivity of current preclinical in vivo models; (iv) the identification and use of a set of cardiotoxic reference compounds for comparative profiling in improved animal and human cellular models; (v) more sharing of data (through publication/consortia arrangements) on target-related toxicities; (vi) strategies to develop cardio-protective agents; and (vii) closer interactions between preclinical scientists and clinicians to help ensure best translational efforts. AbbreviationsABPI, Association for British Pharmaceutical Industry; hESC-CM, human embryonic stem cell-derived cardiomyocyte; HF, heart failure; LVD, left ventricular dysfunction; LVEF, left ventricular ejection fraction; SCD, sudden cardiac death; TKI, tyrosine kinase inhibitor

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

“…Physical damage is primarily associated with drugs specifically designed to be cytotoxic, such as chemotherapeutic agents in cancer treatment (Cross et al , 2015; Ewer and Ewer, 2015). These drugs induce mitochondrial damage (Varga et al , 2015), increase oxidative stress (Cross et al , 2015), activate DNA damage response pathways (Mercurio et al , 2016) and increase apoptosis (Arola et al , 2000). The net outcome for the heart may be many fewer CMs, with a residual proportion being vital but unhealthy.…”

Cardiotoxic drugs Herceptin and doxorubicin inhibit cardiac microvascular endothelial cell barrier formation resulting in increased drug permeability

“…Cardiotoxicity is defined as a severe and potentially fatal adverse cardiovascular event in response to certain drugs and is responsible for the majority of drug development terminations/withdrawals at the pre-clinical and post-approval stage over the last 10 years (Cross et al, 2015; Laverty et al, 2011). Drug induced cardiotoxicity can result in both functional effects such as arrhythmia and acute alteration of the contractile function (inotropy) of the heart, and morphological (structural) damage to the myocardium (Cross et al, 2015).…”

Cardiovascular safety risk assessment for new candidate drugs from functional and pathological data: Conference report

“…), depending on whether it was functional data or pathology being presented, yet it was all about the same topic (cardiovascular safety). Hopefully this meeting acted as a catalyst for those present to adopt multi-disciplinary approaches when addressing cardiovascular safety (Berridge et al, 2013;Cross et al, 2015;Redfern et al, 2013). We also hope that readers of this article will refer to the cited publications to achieve this aim themselves.…”

“…This presentation described and discussed the scale of the problem, what learning we can take from past failures, some of the advances that have been made and potential opportunities for the future. This presentation took us 'beyond the QT interval', something which has arguably been too much of a focus in the past, and onto themes including the principal consideration of this meeting: integrating functional and pathological data to assess adverse effects of drugs on the cardiovascular system (Cross et al, 2015).…”