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: • 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.

International Life Sciences Institute (Health and Environmental Sciences Institute, HESI) initiative on moving towards better predictors of drug-induced torsades de pointes.

Knowledge of the cardiac safety of emerging new drugs is an important aspect of assuring the expeditious advancement of the best candidates targeted at unmet medical needs while also assuring the safety of clinical trial subjects or patients. Present methodologies for assessing drug-induced torsades de pointes (TdP) are woefully inadequate in terms of their specificity to select pharmaceutical agents, which are human arrhythmia toxicants. Thus, the critical challenge in the pharmaceutical industry today is to identify experimental models, composite strategies, or biomarkers of cardiac risk that can distinguish a drug, which prolongs cardiac ventricular repolarization, but is not proarrhythmic, from one that prolongs the QT interval and leads to TdP. To that end, the HESI Proarrhythmia Models Project Committee recognized that there was little practical understanding of the relationship between drug effects on cardiac ventricular repolarization and the rare clinical event of TdP. It was on that basis that a workshop was convened in Virginia, USA at which four topics were introduced by invited subject matter experts in the following fields: Molecular and Cellular Biology Underlying TdP, Dynamics of Periodicity, Models of TdP Proarrhythmia, and Key Considerations for Demonstrating Utility of Pre-Clinical Models. Contained in this special issue of the British Journal of Pharmacology are reports from each of the presenters that set out the background and key areas of discussion in each of these topic areas. Based on this information, the scientific community is encouraged to consider the ideas advanced in this workshop and to contribute to these important areas of investigations over the next several years.

Key clinical considerations for demonstrating the utility of preclinical models to predict clinical drug-induced torsades de pointes.

While the QT/QTc interval is currently the best available clinical surrogate for the development of drug-induced torsades de pointes, it is overall an imperfect biomarker. In addition to low specificity for predicting arrhythmias, other issues relevant to using QT as a biomarker include (1) an apparent dissociation, for some drugs (for example, amiodarone, sodium pentobarbital, ranolazine) between QT/QTc interval prolongation and TdP risk, (2) Lack of clarity regarding what determines the relationship between QTc prolongation and TdP risk for an individual drug, (3) QT measurement issues, including effects of heart rate and autonomic perturbations, (4) the significant circadian changes to the QT/QTc interval and (5) concerns that the development, regulatory and commercial implications of finding even a mild QT prolongation effect during clinical development has significant impact the pharmaceutical discovery pipeline. These issues would be significantly reduced, clinical development simplified and marketing approval for some drugs might be accelerated if there were a battery of preclinical tests that could reliably predict a drug's propensity to cause TdP in humans, even in the presence of QTc interval prolongation. This approach is challenging and for it to be acceptable to pharmaceutical developers, the scientific community and regulators, it would need to be scientifically well validated. A very high-negative predictive value demonstrated in a wide range of drugs with different ionic effects would be critical. This manuscript explores the issues surrounding the use of QT as a clinical biomarker and potential approaches for validating preclinical assays for this purpose against clinical data sets.

A prototypical process for creating evidentiary standards for biomarkers and diagnostics.

A framework for developing evidentiary standards for qualification of biomarkers is a key need identified in the Food and Drug Administration's Critical Path Initiative. This article describes a systematic framework that was developed by Pharmaceutical Research and Manufacturers of America (PhRMA) committees and tested at a workshop in collaboration with the Food and Drug Administration and academia. With some necessary refinements, this could be applied to create an appropriately individualized evidentiary standard for any biomarker purpose.

In vitro screening for antiretroviral agents against simian immunodeficiency virus (SIV).

Simian immunodeficiency virus (SIV), which causes an acquired immunodeficiency syndrome in macaques, is a lentivirus that is morphologically, antigenically, genetically, and biologically similar to the human immunodeficiency virus (HIV). Because of these similarities, the SIV model represents a unique opportunity for in vitro and in vivo testing of antiretroviral agents. Since antiretroviral agents may exhibit different properties in different cells in vitro, more than one cell line may be necessary to evaluate the efficacy and modes of action of an antiretroviral agent. Initially we tested ten cell lines for their permissiveness to five SIV isolates. One B-cell line (AA-2) and one T-cell line (HuT 78) were selected to test antiretroviral agents since both were extremely permissive for SIVmac251, an isolate with a high rate of infectivity. Using this optimized in vitro testing protocol, we screened ten antiretroviral agents for their ability to inhibit SIV replication. Six of the compounds completely inhibited SIV viral antigen expression. Based on the selectivity index, 3'-azido-3'-dideoxythymidine, 3'-azido-2',3'-dideoxyuridine, and 3'-fluoro-3'-deoxythymidine appear to be the most efficacious antiretroviral agents against SIVmac251. Several different assays for determining viral antigen inhibition were conducted and the results of these assays were comparable. Our results demonstrate that the SIV in vitro model is a valuable screening tool for determining the efficacy and toxicity of new antiretroviral agents.