Jean-Pierre Valentin

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

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:

Cardiotoxicity Associated with Targeting Kinase Pathways in Cancer

Cardiotoxicity, also referred to as drug-induced cardiac injury, is an issue associated with the use of some small-molecule kinase inhibitors and antibody-based therapies targeting signaling pathways in cancer. Although these drugs have had a major impact on cancer patient survival, data have implicated kinase-targeting agents such as sunitinib, imatinib, trastuzumab, and sorafenib in adversely affecting cardiac function in a subset of treated individuals. In many cases, adverse cardiac events in the clinic were not anticipated based on preclinical safety evaluation of the molecule. In order to support the development of efficacious and safe kinase inhibitors for the treatment of cancer and other indications, new preclinical approaches and screens are required to predict clinical cardiotoxicity. Laboratory investigations into the underlying molecular mechanisms of heart toxicity induced by these molecules have identified potentially common themes including mitochondrial perturbation and modulation of adenosine monophosphate-activated protein kinase activity. Studies characterizing cardiac-specific kinase knockout mouse models have developed our understanding of the homeostatic role of some of these signaling mediators in the heart. Therefore, when considering kinases as potential future targets or when examining secondary pharmacological interactions of novel kinase inhibitors, these models may help to inform us of the potential adverse cardiac effects in the clinic.

Sex differences in ventricular repolarization: from cardiac electrophysiology to Torsades de Pointes

A number of non‐cardiovascular drugs have been withdrawn from clinical use due to unacceptable adverse cardiac side‐effects involving drug‐induced Torsades de Pointes (TdP) – a rare, life‐threatening polymorphic ventricular tachycardia associated with prolongation of the action potential duration of ventricular myocytes and, hence, prolongation of the QT interval, of the electrocardiogram (ECG), which measures the total time for activation of the ventricles and their recovery to the resting state. Research has suggested that women are more prone to develop TdP than men during administration of medicines that share the potential to prolong the QT interval, with 65–75% of drug‐induced TdP occurring in women.

Scientific review and recommendations on preclinical cardiovascular safety evaluation of biologics.

Biological therapeutic agents (biologicals), such as monoclonal antibodies (mAbs), are increasingly important in the treatment of human disease, and many types of biologicals are in clinical development. During preclinical drug development, cardiovascular safety pharmacology studies are performed to assess cardiac safety in accord with the ICH S7A and S7B regulations that guide these studies. The question arises, however, whether or not it is appropriate to apply these guidelines, which were devised primarily to standardize small molecule drug testing, to the cardiovascular evaluation of biologicals. We examined the scientific literature and formed a consensus of scientific opinion to determine if there is a rational basis for conducting an in vitro hERG assay as part of routine preclinical cardiovascular safety testing for biologicals. We conclude that mAb therapeutics have very low potential to interact with the extracellular or intracellular (pore) domains on hERG channel and, therefore, are highly unlikely to inhibit hERG channel activity based on their targeted, specific binding properties. Furthermore, mAb are large molecules (>140,000 Da) that cannot cross plasma membranes and therefore would be unable to access and block the promiscuous inner pore of the hERG channel, in contrast with typical small molecule drugs. Consequently, we recommend that it is not appropriate to conduct an in vitro hERG assay as part of a preclinical strategy for assessing the heart rate corrected QT interval (QTc) prolongation risk of mAbs and other types of biologicals. It is more appropriate to assess QTc risk by integrating cardiovascular endpoints into repeat-dose general toxicology studies performed in an appropriate non-rodent species. These recommendations should help shape future regulatory strategy and discussions for the cardiovascular safety pharmacology testing of mAbs as well as other biologicals and provide guidance for the preclinical cardiovascular evaluation of such agents.

Current challenges in the evaluation of cardiac safety during drug development: Translational medicine meets the Critical Path Initiative

In October 2008, in a public forum organized by the Cardiac Safety Research Consortium and the Health and Environmental Sciences Institute, leaders from government, the pharmaceutical industry, and academia convened in Bethesda, MD, to discuss current challenges in evaluation of short- and long-term cardiovascular safety during drug development. The current paradigm for premarket evaluation of cardiac safety begins with preclinical animal modeling and progresses to clinical biomarker or biosignature assays. Preclinical evaluations have clear limitations but provide an important opportunity to identify safety hazards before administration of potential new drugs to human subjects. Discussants highlighted the need to identify, develop, and validate serum and electrocardiogram biomarkers indicative of early drug-induced myocardial toxicity and proarrhythmia. Specifically, experts identified a need to build consensus regarding the use and interpretation of troponin assays in preclinical evaluation of myocardial toxicity. With respect to proarrhythmia, the panel emphasized a need for better qualitative and quantitative biomarkers for arrhythmogenicity, including more streamlined human thorough QT study designs and a universal definition of the end of the T wave. Toward many of these ends, large shared data repositories and a more seamless integration of preclinical and clinical testing could facilitate the development of novel approaches to both cardiac safety biosignatures. In addition, more thorough and efficient early clinical studies could enable better estimates of cardiovascular risk and better inform phase II and phase III trial design. Participants also emphasized the importance of establishing formal guidelines for data standards and transparency in postmarketing surveillance. Priority pursuit of these consensus-based directions should facilitate both safer drugs and accelerated access to new drugs, as concomitant public health benefits.

A rabbit Langendorff heart proarrhythmia model: predictive value for clinical identification of Torsades de Pointes.

The rabbit isolated Langendorff heart model (SCREENIT) was used to investigate the proarrhythmic potential of a range of marketed drugs or drugs intended for market. These data were used to validate the SCREENIT model against clinical outcomes.

Safety and secondary pharmacology: Successes, threats, challenges and opportunities

This review summarises the lecture of Dr Tim Hammond, recipient of the Distinguished Service Award of the Safety Pharmacology Society, given on 20 September 2007 in Edinburgh. The lecture discussed the rationale behind the need for optimal non-clinical Safety and Secondary Pharmacology testing; the evolution of Safety and Secondary Pharmacology over the last decade; its impact on drug discovery and development; the value of adopting an integrated risk assessment approach; the translation of non-clinical findings to humans and finally the future challenges and opportunities facing these disciplines.

A framework to assess the translation of safety pharmacology data to humans

This article outlines a strategy for collecting accurate data for the determination of the sensitivity, specificity and predictive value of safety pharmacology models. This entails performing a retrospective analysis on commonly used safety pharmacology endpoints and an objective assessment of new non-clinical models. Such assessments require a systematic quantitative analysis of safety pharmacology parameters as well as clinical Phase I adverse events. Once the sensitivity, specificity and predictive capacity of models have been determined, they can be aligned within specific phases of the drug discovery and development pipeline for maximal impact, or removed from the screening cascade altogether. Furthermore, data will contribute to evidence-based decision-making based on the knowledge of the model sensitivity and specificity. This strategy should therefore contribute to the reduction of candidate drug attrition and a more appropriate use of animals. More data are needed to increase the power of analysis and enable more accurate comparisons of models e.g. pharmacokinetic/phamacodynamic (PK/PD) relationships as well as non-clinical and clinical outcomes for determining concordance. This task requires the collaboration and agreement of pharmaceutical companies to share data anonymously on proprietary and candidate drugs.

IKs restricts excessive beat-to-beat variability of repolarization during beta-adrenergic receptor stimulation

In vivo studies have suggested that increased beat-to-beat variability of ventricular repolarization duration (BVR) is a better predictor of drug-induced torsades de pointes than repolarization prolongation alone. Cellular BVR and its dynamics before proarrhythmic events are poorly understood. We investigated differential responses of BVR in single myocytes during I(Ks) blockade versus I(Kr) blockade and late-I(Na) augmentation, under the influence of beta-adrenergic receptor stimulation. Transmembrane action potentials were recorded from isolated canine left-ventricular midmyocytes at various pacing rates. I(Ks) was blocked by HMR1556, I(Kr) by dofetilide. Late I(Na) was augmented by sea anemone toxin-II. Isoproterenol was added for beta-adrenergic receptor stimulation. BAPTA-AM buffered intracellular Ca(2+). SEA0400 partially inhibited the Na(+)-Ca(2+) exchanger. BVR was quantified as variability of action-potential duration at 90% repolarization: Sigma(|APD90; i+1 minus APD90; i|)/[nbeatsx radical2] for 30 consecutive action potentials. Baseline BVR was significantly increased by I(Kr) blockade and late-I(Na) augmentation, especially at slow pacing rates. beta-adrenergic stimulation restabilized these BVR changes. In contrast, I(Ks) blockade caused very little change in repolarization when compared to baseline conditions, but predisposed the myocyte to increased BVR during beta-adrenergic stimulation, especially at fast rates. BAPTA-AM and SEA0400 reduced this excessive BVR and eliminated early afterdepolarizations. In conclusion, beta-adrenergic receptor stimulation exaggerates BVR during I(Ks) blockade, indicating a BVR-stabilizing role of beta-adrenergic-sensitive I(Ks). Loss of I(Ks) plus overriding of Ca(2+)-dependent membrane currents, including inward Na(+)-Ca(2)(+) exchange current, conspire to proarrhythmic BVR under these conditions.

Zebrafish assays as early safety pharmacology screens: Paradigm shift or red herring?

The recent flurry of interest in the potential use of the zebrafish (Danio rerio) in Drug Discovery has also led to the development of a range of assays purported to be useful as early screens in safety pharmacology. The purpose of this commentary is to take stock of the available zebrafish assays in the context of alternative mammalian cell-based assays, and of the validation outcomes to date. In addition, we report the results of a recent survey of the membership of the Safety Pharmacology Society regarding their views on zebrafish assays. The survey data indicate that the preferred way forward would be a collaborative effort between the pharmaceutical/biotechnology industry (as potential/eventual customers), and the zebrafish contract research companies (as suppliers), alongside expert input from academia and regulatory authorities.