Cardiac toxicity is one of the leading causes of drug attrition during development. Detecting cardiovascular (CV) safety issues earlier in drug development would produce significant benefits for pharmaceutical companies and public health. Animals surgically instrumented with telemetry devices can be used as screening tools for cardiac toxicity during the drug selection process. Phil Atterson, director of Pharmacology, Cardiovascular Sciences and Specialty Toxicology Services at WIL Research, talked with us about the latest telemetry instrument advances and how they can be used as screening tools earlier in the drug selection phase.
Contract Pharma: What kinds of information are you looking for in telemetry studies?
Phil Atterson: Advancements in telemetry capabilities and surgical techniques facilitate the capture of identical endpoints (with equivalent signal quality) in conscious, non-restrained subjects, compared to that of anesthetized subjects. These data include a range of acute hemodynamic and cardiac parameters such as heart rate, blood pressure (systolic, diastolic and calculated mean) and pulse pressure, electrocardiogram (ECG), ventricular contractility, etc. The industry trend during development has been favoring the use of conscious, freely moving, telemetry-instrumented animals to acquire these parameters.
Chronic effects — those seen with long-term administration of the NCE to an intact organism — are also monitored during safety studies. ECGs are collected to evaluate the chronic cardiac effects in non-rodent species during Phase I and II. While traditional ECGs can be taken, we recommend use of jacketed external telemetry (JET) techniques, which permit the recording of ECGs — but not blood pressure — in freely moving animals. Such systems negate the stress responses associated with the handling and restraint procedure and, with improved sensitivity, allow for a more thorough evaluation of drug-induced changes. In addition, the JET system allows for longer recording periods, which lends itself to a more robust analysis.
CP: What advantages do telemetry-based studies provide over non-telemetry studies?
PA: Telemetry-based systems offer advantages compared to standard, restrained or anesthetized paradigms in that the data are acquired from freely moving animals over greater durations without anesthetic in the test system, which has the potential to confound and perturb results interpretation. An advantage of telemetry studies is that the animals can be left undisturbed for critical periods, removing excitation artifacts from the data set. Furthermore, implanted animals can also be reused, following a suitable wash-out period, providing an excellent resource for screening compounds to detect unwanted side effects. This also allows us to perform latin square/ cross over designed studies, which increases statistical power while utilizing the minimum number of animals.
CP: What are some recent advances in telemetry devices and what do they measure for?
PA: Recent advancements in telemetry development allow for concurrent evaluation of CV and respiratory endpoints (via impedance) for a complete cardio respiratory evaluation in a single subject. This advancement enables researchers to make a direct correlation between CV and respiratory function in contrast to such comparisons being drawn from multiple studies with potentially different species used in each evaluation.
Additional advancements also enable the evaluation of CNS function via implanted EEG biopotential leads. Such recordings would be performed simultaneously with the CV evaluation.
Employment of the above collection paradigms provides a reduction in the number of animals, and potentially shortened timelines with a single study for evaluation of multiple endpoints. Of greatest importance, such evaluations allow for a more thorough scientific evaluation, thus providing a greater risk assessment prior to clinical trials.
CP: What kind of information does this new data provide for drug makers looking to shorten and/or reduce the burden of their development programs?
PA: The use of telemetry-instrumented animals coupled with recent advances in software-analysis systems allow for rapid data turnaround, enabling scientists to quickly determine if there are any potentially unwanted signals. If any effects are detected on, for example, blood pressure or QT interval prolongation, then the decision to either shelve the drug or conduct additional studies can be made before advancing any further in the developmental phase.
Interestingly, the experience that has been acquired since the approval of the ICH guidelines related to cardiac risk (ICH S7A and ICH S7B) has allowed pharma companies to temper their response to finding a potentially unwanted signal. Rather than permanently shelve libraries of compounds that, for example, were found to be positive in the hERG assay — common practice when the 2005 guidelines came into being — companies can now determine a risk potential based on knowledge gained with the intact animal studies.
CP: What are potential limitations and considerations researchers should understand before engaging in telemetry studies?
PA: There are a number of factors that come into play when performing telemetry studies. First, the model requires a very experienced and competent surgery group to ensure that the device is correctly placed to provide high quality signals. In addition, the copious amount of data generated requires the support of an experienced IT group to allow navigation through the study output. Finally, an in-depth understanding of CV pharmacology is crucial in allowing for the correct interpretation of the data. It is not a service to be considered lightly.
CP: Care to make any predictions about how drug companies can improve their ability to predict potential cardiac events?
PA: As the focus on cardiac safety has matured over the last 10 years, the Safety Pharmacology Society has led efforts to determine best practices for conducting key preclinical cardiovascular assessments in drug development. From this, the hope is to provide sensitive preclinical assays that can detect high-probability safety concerns.
Parallel efforts have been made to more accurately assess the translation of preclinical cardiovascular data into clinical outcomes and to encourage collaborations between preclinical and clinical scientists involved in cardiac safety assessment. The International Life Science Institute–Health and Environmental Services Institute (ILSI-HESI) consortium has bought together industrial, academic, and government scientists to determine what steps are necessary to establish an integrated cardiovascular safety assessment program. The goal is to provide better ways of predicting potential adverse events, allowing for earlier detection of cardiovascular safety issues and reducing the number of clinical trial failures.
Gil Roth has been the editor of Contract Pharma since its debut in 1999. He can be reached at firstname.lastname@example.org.