Beyond the safety assessment of drug-mediated changes in the QT interval... what's next?

Assessing drug-induced changes (particularly prolongation) in the QT interval has been the major preoccupation of safety pharmacology since its inception, under the assumption that QT widening represents a surrogate biomarker for torsades de pointes (TdeP) liability. While evidence of changes in QT remains a bane to the development of novel therapeutic agents, non-clinical and clinical methods have been developed (with a certain amount of validation) to limit this potential liability of a new chemical entity (NCE). Because of the associated withdrawal of numerous drugs from clinical use, determining whether or not a drug development candidate exhibits a TdeP liability has been the motivation in the implementation of discussions between 'pharmaceutical companies', academicians, clinicians and regulatory authorities worldwide that has led to the development of the ICHS7A and ICHS7B guidance documents (Anon, 2001, 2005). Simultaneously, it has resulted in the firm establishment of safety pharmacology as a standalone discipline within the drug development scheme (Pugsley et al., 2008). As far as TdeP liability is concerned, QT widening remains the most poignant issue, in that QT widening in humans is immediately regarded as a cause for concern, yet QT widening in preclinical models (and indeed in man) is not a quantitative predictor of TdeP liability (and indeed may not even be a qualitative predictor by itself (Pugsley et al., 2008). The present focused issue of the journal returns to safety pharmacology, and contains papers arising from the 8th annual SPS Meeting that was held in Madison, WI in 2008. Indeed, so many papers have arisen from the meeting that this issue of the Journal is only part 1. Part 2 will be published as the next issue of the Journal. Some topics which have been addressed include whether an assessment method for drugs that produce a shortened QT interval is needed, what the role of the slow component of the delayed rectifier K current (I(Ks)) should be in a safety assessment and whether safety pharmacology endpoints can or should be added to repeat dose Toxicology studies.

Blockade of the I(Ks) potassium channel: an overlooked cardiovascular liability in drug safety screening?

The problem of drug-induced hERG channel blockade, which can lead to acquired long QT syndrome and potentially fatal arrhythmias, has exercised drug developers and regulatory authorities for over 10 years, and exacting guidelines have been put into place to test for this liability both preclinically (ICH S7B) and clinically (ICH E14). However, the I(Ks) channel, which along with the transient outward current (I(to)) is the other main potassium channel affecting cardiac repolarisation and thus the length of the QT interval, has received little attention, and potent I(Ks) blocking drugs with serious side effects could potentially enter into human testing without being detected by the existing regulatory core battery and standard screening strategies. Here we review the pharmacology of cardiac I(Ks) channel blockade and describe the discovery of a potent I(Ks) blocker whose activity was not detected by standard hERG or invitro action potential screens, but subsequently evoked unprovoked torsades de pointes (TdP) invivo in our anaesthetised dog model. We have exploited this molecule to develop a ligand binding assay to detect I(Ks) blockade at an earlier stage in drug discovery, and note that several other laboratories developing new drugs have also developed higher throughput screens to detect I(Ks) blockade (e.g., [Trepakova, E. S., Malik, M. G., Imredy, J. P., Penniman, J. R., Dech, S. J., & Salata, J. J. (2007) Application of PatchXpress planar patch clamp technology to the screening of new drug candidates for cardiac KCNQ1/KCNE1 (I(Ks)) activity. Assay Drug Development Technology 5, 617-627]). Because of the presence of I(Ks) channels in other tissues, including blood vessels and in the epithelia of intestine, kidney, lung and the cochlea, I(Ks) blockade has the potential to cause extensive side effects in addition to QT prolongation and arrhythmias. We therefore suggest that compounds selected for development should also be examined for I(Ks) liability before testing in humans. The possibility of undetected I(Ks) blockade is therefore an additional gap to that identified earlier [Lu, H. R., Vlaminckx, E., Hermans, A. N., Rohrbacher, J., Van Ammel, K., Towart, R., et al. (2008) Predicting drug-induced changes in QT interval and arrhythmias: QT-shortening drugs point to gaps in the ICH S7B Guidelines. British Journal of Pharmacology, 154, 1427-1438] in the ICH S7B regulatory guidelines.

Methods in safety pharmacology in focus.

This focused issue of the Journal of Pharmacological and Toxicological Methods is the fifth to highlight Methods in Safety Pharmacology and includes a number of articles from the 7th Annual Safety Pharmacology Society (SPS) meeting that was held in Edinburgh, Scotland, September 19-21, 2007. However, unlike issues of the past, in which content predominantly focused on cardiovascular issues (specifically QT interval prolongation, QT-HR correction methods and validation of non-clinical cardiovascular models) this issue is composed of a number of non-cardiovascular methods papers and review articles. Of particular interest to readers will be articles related to CNS studies, in particular neurobehavioral assessments in non-human primates and the effects of drugs in juvenile and adult rats (an article that may be relevant in light of recent EU/US pediatric legislation). While cardiovascular function may not dominate there are several useful methodological papers including an assessment of cardiovascular sensitivity of drugs in conscious and anesthetized non-human primates, and a mathematical model (fractal analysis) applied to canine heartbeat dynamics. A first for the journal is a paper by Vargas et al., (2008-this issue) in which members of the SPS formed a working group in order to assess and review safety pharmacology testing of biological therapeutic agents (specifically monoclonal antibodies, mAbs). The group provides recommendations that will likely shape regulatory strategy and discussions in the yet to be fully discussed area of biological safety testing. In the tradition of obtaining a perspective on industry safety pharmacology program practices Lindgren et al., (2008-this issue) provide the results of a recent SPS survey that examines ICH S7A and S7B trends, aspects of early 'frontloading' safety studies, abuse and dependence liability and Contract Research Organization (CRO) tests/assays used in safety assessment of core battery and supplementary organ systems. In keeping with the translation track aspect of the 2007 meeting is an overview of the Distinguished Service Award lecture to Dr. T. Hammond that discusses many aspects of safety pharmacology including its evolution, impact, value and translation of non-clinical findings to humans. Finally, perspectives are presented on the use of the zebrafish as an early safety pharmacology-screening assay.