cardiovascular toxicity: understanding the issues, challenges and opportunities

Abstracts / Toxicology Letters 221S (2013) S4–S30 S23

S13-5New insights in the management of toxic acutelung injury

Dylan de Lange

Clinical Toxicology and ICU, University Medical Center, Utrecht, TheNetherlands

Extracorporeal membrane oxygenation (ECMO) can be veryuseful to support organ function in severe intoxicated patients.Although ECMO has been used in many patients since its intro-duction in 1972 most institutes had abandoned this experimentaltreatment for adult patients. Recently, improvements in the ECMOcircuitry rendered it more biocompatible. In the Influenza A/H1N1pandemic of 2009 many patients with severe acute respiratory dis-tress syndrome (ARDS) were treated with ECMO. These patientshad a surprisingly low mortality. This resurrected the interest inECMO in many ICU’s around the world.

We will discuss the different modes of ECMO, the indications,complications, and outcome of studies on ECMO. Basically, twotypes of ECMO are used: veno-venous ECMO (VV-ECMO) or veno-arterial ECMO (VA-ECMO). VV-ECMO is used for patients withsevere ARDS to secure adequate oxygenation of the organs whileprotecting the lungs from harmful ventilation pressures or pro-longed inspiratory fraction of oxygen. VA-ECMO could be usedwhenever the patient remains in shock despite adequate fluidresuscitation and is refractory to administration of inotropes andvasopressors. The organ support that can be applied with ECMOmakes it especially useful in patients with severe intoxications.Often intoxications are temporary and ECMO can be used as “bridgeto recovery”. However, ECMO is associated with some severe com-plications and should, therefore, be reserved for the most severelyill patients with a high risk of mortality.

http://dx.doi.org/10.1016/j.toxlet.2013.06.080

Symposium 14: Cardiovascular toxicity in drug discovery anddevelopment

S14-1Cardiovascular toxicity: understanding theissues, challenges and opportunities

Rashmi R Shah

Rashmi Shah Consultancy Ltd, Gerrards Cross, United Kingdom

The efforts at characterising new drugs for their cardiovasculartoxicity have hitherto focussed on their proarrhythmic potential,particularly their effect on cardiac repolarization, typically involv-ing a thorough QT study. Attention given to this study has fosteredan illusion that the electrophysiologic safety it characterises is syn-onymous with clinical cardiac safety. Unfortunately, this study aimsto characterise very precisely a parameter, the rate-corrected QTinterval, which lacks the required sensitivity and specificity to pre-dict the clinical risk that really matters. Experience with nearly 300such studies raises the question whether the role of this study hasnow been played out since (a) it is not cost-effective, (b) clinicallyequally valuable information can be obtained from ECG record-ings during multiple ascending dose studies and (c) a battery ofnon-clinical studies successfully identifies clinical torsadogens. Theintroduction of new pharmacological classes of drugs has thrownup further challenges to characterising cardiac toxicity of drugs.For example, the development of torcetrapib was halted becauseof excess mortality, probably due to its effect on blood pressure.

Tyrosine kinase inhibitors have emerged as a new class of oncologydrugs. Twenty have been currently approved with a further approx-imately 50 under development. Their use is associated with a wholerange of cardiovascular toxicities. Since these agents are expectedto be used widely, they present new challenges and opportuni-ties for a broader approach to defining the cardiac toxicity of newdrugs. A greater challenge lies in their risk/benefit analysis sincethey are indicated for the management of advanced cancers withonly modest benefits.

http://dx.doi.org/10.1016/j.toxlet.2013.06.082

S14-2Hazard identification and elimination:designing safe medicines

Laszlo Urban

Preclinical Safety Profiling, NIBR, Cambridge, MA, USA

High attrition rate of drug candidates and market withdrawalof drugs due to safety issues is a major burden on the pharma-ceutical industry and society. While regulatory preclinical safetyassessment is mandatory for all drug candidates, it comes late andhas several shortfalls, such as species differences and limitations bydosing or duration of drug administration. Recent development ofpreclinical safety pharmacology and pathway profiling has beendesigned to identify safety hazards earlier during the drug dis-covery process with primary focus on human targets. This wasmade possible by identification and association of proteins withadverse drug reactions (ADRs) and profile compounds in in vitroassays based on these targets (Whitebread et al., 2005; Boweset al., 2012). Once hazards are identified, iterative assessment atthe suspect target can provide support for SAR-based mitigation.Data obtained from the profiling assays are integrated with efficacyinformation (usually free effective Cmax) to predict safety windowfor the molecule. In vitro safety profiling has been complementedwith predictive in silico tools in recent years to further enhance itsefficacy.

This process, based on hazard mitigation can successfully guideand reduce safety management of drug candidates.

Reference

Bowes, J., Brown, A.J., Hamon, J., Jarolimek, W., Sridhar, A., Waldron, G., Whitebread,S., 2012. Reducing safety-related drug attrition: the use of in vitro pharmaco-logical profiling. Nature Reviews Drug Discovery 11, 909–922.

Whitebread, S., Hamon, J., Bojanic, D., Urban, L., 2005. In vitro safety pharmacol-ogy profiling: an essential tool for drug development. Drug Discovery Today 10,1421–1433.

http://dx.doi.org/10.1016/j.toxlet.2013.06.083

S14-3Integrated cardiovascular risk assessment: abalancing act between risk and benefits

Tim G. Hammond 1, Jean-Pierre Valentin 2

1 Preclinical Safety Consulting Ltd., UK, 2 Global Safety Assessment,AstraZeneca, UK

Cardiovascular toxicity remains a major reason for failure dur-ing drug development and significant cause of drug withdrawalpost marketing. The complexity of the cardiovascular system,involving the heart, vasculature and blood components providemultiple opportunities for beneficial intervention but paradoxically