Ray W. Chui

Assessment of two external telemetry systems (PhysioJacket™ and JET™) in beagle dogs with telemetry implants

INTRODUCTION Regulatory guidelines recommend the use of conscious, unrestrained animals for comprehensive cardiovascular safety assessment of a new therapeutic agent. Cardiovascular safety pharmacology studies normally use internal telemetry (surgical implants) in free-moving animals to monitor key ECG endpoints, like the QTc interval, but this technical approach is highly resource intensive. In toxicology studies, ECG recording is also typically performed under chemical or physical restraint, which has a number of disadvantages, e.g., anesthesia confounds, handling stress and limited data collection. External telemetry for ECG recording has the potential to overcome many of these restraint limitations, with the benefit of being a surgically non-invasive method. To evaluate this method, we used two jacket systems: Data Sciences International (DSI) JET and Integrated Telemetry Systems (ITS) PhysioJacket in implanted beagle dogs. METHODS Heart rate and cardiac intervals were monitored continuously for 22-24 h following oral administration of vehicle (water) or 1 mg/kg E-4031. Data obtained from each jacket system was compared with implant-derived data in the same animal. RESULTS Significant increases in QT/QTcV (25-30 ms) were noted following treatment with 1 mg/kg E-4031 in both external jacket systems and with implanted telemetry. Throughout the recording periods, the normal variations in heart rate and ECG intervals observed in conscious dogs as detected with the jacket systems, mirrored the changes observed via implant telemetry. DISCUSSION The overall findings from this study support the use of external telemetry technology as a viable alternative to implants. The data demonstrated that jackets were sufficiently sensitive to detect QT/QTcV changes following E-4031 administration, that were comparable to those derived from implants. As such, this method is an invaluable tool for obtaining high quality ECG data from repeat-dose toxicology studies.

BeKm-1, a Peptide Inhibitor of Human ether-a-go-go-Related Gene Potassium Currents, Prolongs QTc Intervals in Isolated Rabbit Heart

Drug-induced cardiac arrhythmia, specifically Torsades de pointes, is associated with QT/QTc interval prolongation, thus prolongation of the QT interval is considered as a biomarker for Torsades de pointes risk (N Engl J Med 350:1013–1022, 2004). Specific inhibition of human ether-a-go-go-related gene (hERG) potassium channels has been recognized as the main mechanism for QT prolongation (Cardiovasc Res 58:32–45, 2003). This mechanism has been demonstrated for a variety of small-molecule agents, which access the inner pore of the hERG channel preferentially from inside the cell. Peptide inhibitors of hERG, such as BeKm-1, interact with the extracellular amino acid residues close to the external pore region of the channel. In this study, the isolated rabbit heart was used to assess whether BeKm-1 could induce QTc prolongation like dofetilide and N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide (E-4031). Five hearts were perfused with 10 and 100 nM BeKm-1 sequentially. ECG parameters and left ventricular contractility were measured with spontaneously beating hearts. Both concentrations of BeKm-1 prolonged QTc intervals significantly and concentration-dependently (4.7 and 16.3% at 10 and 100 nM, respectively). When evaluated for their inhibitory effect in a hERG functional assay, BeKm-1, dofetilide, and E-4031 caused QTc prolongation at concentrations that caused significant hERG channel inhibition. Lastly, two polyclonal anti-hERG antibodies were also assessed in the hERG channel assay and found to be devoid of any inhibitory effect. These results indicated that the isolated rabbit heart assay can be used to measure QTc changes caused by specific hERG inhibition by peptides that specifically block the external pore region of the channel.

Detection of QTc interval prolongation using jacket telemetry in conscious non-human primates: comparison with implanted telemetry

During repeat‐dose toxicity studies, ECGs are collected from chemically or physically‐restrained animals over a short timeframe. This is problematic due to cardiovascular changes caused by manual restraint stress and anesthesia, and limited ECG sampling. These factors confound data interpretation, but may be overcome by using a non‐invasive jacket‐based ECG collection (JET). The current study investigated whether a jacketed external telemetry system could detect changes in cardiac intervals and heart rate in non‐human primates (NHPs), previously implanted with a PCT transmitter.

A comparison of three software platforms for automated ECG analysis

INTRODUCTION Current regulatory guidelines attempt to standardize the models used to assess the safety aspects of new test compounds. However, they do not address the means of deriving the critical data. With the increased data volume that is a result of more extensive safety scrutiny and continuous data assessment, especially in cardiovascular telemetry studies, there is a clear need to assess the automated ECG analysis tools currently available on the market. METHODS Cardiovascular studies were conducted using implanted beagle dogs following the oral administration of E-4031 (0 and 1 mg/kg) and the animals were monitored for 22-24 h post-dose. The raw ECG data trace was converted into file formats accessible by Data Sciences International (DSI) Ponemah with pattern recognition option (PRO), EMKA ecgAuto and Notocord HEM. RESULTS Validation using a reference signal generator showed comparable performance by the applications being evaluated. Significant increases in QT/QTcV (25-40 ms) were noted following treatment with 1 mg/kg E-4031 (T(max)</=0.5 h). All software applications showed similar trends in QT/QTcV analyses. DISCUSSION The choice of analysis applications is dependent on a number of variables, e.g., animal model used, the need for real-time analysis and visualization, flexibility, learning curve, etc. In our study, similar trends were observed for all three ECG software applications, but pattern recognition approaches were more amenable to adapting to ECG morphology changes over the course of 24 hour telemetry study.