“Covering” Cardiovascular Safety in Repeat-Dose Studies
Safety Assessment
Robert Kaiser

“Covering” Cardiovascular Safety in Repeat-Dose Studies

Jacketed external telemetry (JET) is the latest technology available for collection of continuous electrocardiograms (ECGs) from unrestrained animals. It delivers higher‑quality cardiovascular safety data than predecessor external technologies and has become a premier solution for preclinical research without the use of invasive implantation techniques. After all, Cardiovascular Safety Pharmacology is a logical target as a persistent goal in the preclinical market is to integrate diverse endpoints into reduced numbers of overall studies.

This door was cracked by the original ICH guideline governing safety pharmacology (S7A) where “the use of new technologies and methodologies in accordance with sound scientific principles is encouraged” and is now kicked open based on revisions to ICH guideline S6 (R1). The revisions state that safety pharmacology “may be investigated in separate studies or incorporated in the design of toxicity studies” for biotechnology-derived products. In the context of these guidelines, JET makes perfect sense as an add-on to repeat dose studies.

The incorporation of electrocardiogram and/or blood pressure measurements in repeat-dose toxicology studies has typically involved the use of “snapshot” data collections performed on conscious, restrained animals, generally yielding 30-120 seconds of data. These data are subject to high variability and are of limited probative value due to the short interval sampled and complicating (even confounding) effects of sympathetic stimulation of the animals during the data acquisition process. While the aforementioned ECGs may be useful for the detection of overt abnormalities, such as grossly irregular heart rates or acutely life-threatening arrhythmias, it is difficult to accurately evaluate possible drug-mediated effects on ECGs (or BP) in the presence of restraint-induced increases in sympathetic tone, which may potentially mask subtle effects.

Continuous data offer significant advantages over the snapshot approaches described above. For example, prolonged, continuous pre-study data collection (typically up to 24 hours) allows for the calculation and application of individual animal rate corrections for assessing QT interval changes, offering increased sensitivity to discern true pharmacological changes in ventricular repolarization kinetics (of utmost toxicological relevance) from procedurally- or pharmacologically-induced primary effects on heart rate.

Further, in species with significant diurnal variations (i.e., reduced heart rate during sleep) telemetry allows for assessment of cardiovascular changes in very stable data streams from undisturbed animals, offering a sensitive assessment of possible drug effects in a model not feasible with manually‑restrained approaches.

For laboratories offering continuous data collection, however, it has historically been necessary to implant animals with telemetry devices to get this caliber of data. Although arguably still the gold-standard in cardiovascular safety assessment, implantation requires an invasive surgery performed in larger animals to accommodate the steric size of the units. Invasive surgery requires additional study lead time to allow for adequate post-surgical convalescence of the test subjects, while using large animals requires increased amounts of test article to dose them for the duration of IND-enabling studies.

Charles River offers JET (Data Sciences, International) to address the need for continuous ECG data collection within the context of the GLP-compliant repeat dose toxicology study, while avoiding the downsides of implantation described above. Importantly, this approach provides data that address the missing link in stand-alone approaches, assessment of repeat exposures and potential accumulation of either test article or toxicologically-relevant metabolites in the test system. To address the need for hemodynamic investigation, Charles River has also validated the BP component of JET and addressed residual concerns of drug developers which prefer not to implant animals by demonstrating that neither the transmitter nor indwelling arterial catheter caused any gross or systemic histologic effects (abstract presented at the 2013 Society of Toxicology meeting, San Antonio, TX). With the addition of this transducer, the JET system can be used to simultaneously collect ECGs and BP from unrestrained animals, capturing all of the advantages previously described for ECGs with the addition of high fidelity peripheral hemodynamic data.

Although jacketed ECG and blood pressure technology will not replace the sensitivity of the fully-implantable stand-alone telemetry model, it does provide researchers with a sensitive tool to detect subtle cardiovascular effects in repeat-dose toxicology studies. By integrating these assessments into the obligate repeat-dose toxicology study designs, drug developers can reduce animal use by reducing the number of studies; generate both acute and chronic safety data to assess the effects of both primary exposure and multiple exposures; evaluate other mechanisms of toxicity that may involve delayed effects; and ensure that exposures are directly comparable between the safety and toxicology data as they are simultaneously generated in the same animals.