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Repeat dose toxicology studies are typically conducted to characterize the structural (physical / pathology related) effects of a test article following repeated administration. Such studies are intended to identify target organs, exposure / response relationships, and potential reversibility of toxic effects. This information is required as part of the safety assessment supporting the conduct of human clinical trials.


Although not required, for many years researchers have included a functional (performance) assessment of the cardiovascular system by collecting 30 seconds to 2 minutes of ECG data using hardwired systems.


In recent years, many researchers have chosen to include 24-hour continuous assessment of functional effects in these studies as a means of providing an improved risk assessment. The functional endpoints most commonly included are those typically collected as part of the core battery of Safety Pharmacology studies (ICH S7A, S7B); especially the cardiovascular endpoints available from ECG and blood pressure measurements.


One advantage of 24-hour continuous assessment of functional endpoints in repeat dose toxicology studies is the ability to collect better data -- data from conscious, free roaming animals that are not confounded by anesthesia or response to human factors. In this manner, the data more closely represents the clinical situation.


Additional advantages of this advanced approach include the ability to provide a more comprehensive assessment of the cumulative effect of a test article on functional endpoints (something not currently required by guidelines) and the opportunity to use animals more efficiently thus supporting the NC3Rs initiative.


A final advantage of this approach is that it is sometimes possible to omit the need for a separate safety pharmacology study. This advantage is most commonly specific to the development of new biological entities since they do not allow for a traditional Latin Square safety pharmacology assessment and instead require a parallel dose design.


In all cases, whenever adding a functional assessment into repeat dose toxicology studies it is recommended that the studies have the sensitivity to detect, or more importantly rule-out, unwanted drug effects. As such, nonclinical studies should be as sensitive as possible within the constraints of protecting the welfare of the animal subjects and reasonable drug development costs.

The collection of functional cardiovascular endpoints, such as ECG and blood pressure, are most commonly achieved using Jacketed External Telemetry (JET™), Implantable Telemetry, or Hardwired Instrumentation.

 

Jacketed External Telemetry

Functional endpoints are collected from conscious, freely moving animals wearing a jacket that contains and protects a small JET device capable of monitoring cardiovascular data and transmitting data to an acquisition and analysis computer system.

 

ECG data are collected via the placement of electrodes on the exterior of the animal that are connected to the JET Device.  Numerous derived endpoints are available from the ECG but the most commonly evaluated are Heart Rate, RR Interval, and the QT Interval with associated corrections.

 

Blood pressure data are collected via the placement of a Minimally Invasive Blood Pressure (MIBP) implant in an artery of the animal.  This implant then transmits to a small antenna connected to the JET Device.  The most commonly evaluated endpoints are systolic, diastolic, and mean arterial pressures, pulse rate, and pulse pressure.

 

 

Implantable Telemetry

Functional endpoints are collected from conscious, freely moving animals that have a small device implanted into them that is capable of monitoring ECG, Blood Pressure, Temperature, and Activity data and transmitting data to an acquisition and analysis computer system.

 

 

Hardwired Instrumentation

Short durations of functional endpoints are collected from chemically or physically restrained animals that are connected to external devices capable of monitoring ECG and recording directly into an acquisition and analysis computer system.

 

Jacketed External Telemetry

DSI’s Jacketed External Telemetry (JET) system was designed for use in repeat dose toxicology studies.  The system is customizable to provide multiple leads of ECG, blood pressure, respiratory rate and volume, external temperature, and activity.

 

JET Systems include:

 

  

Implantable Telemetry

DSI offers two large animal implantable telemetry systems suitable for use in repeat dose toxicology studies.  The PhysioTel Digital System is the newest and most advanced system offering group-housing capability.  The PhysioTel System is our basic system and does not allow for group housing.

 

PhysioTel Digital Systems include:

PhysioTel Systems include:

Hardwired

DSI offers two hardwired ECG options suitable for use in repeat dose toxicology studies.  The Multi-lead ECG Pod is able to provide 12 leads of ECG from a standard industry patient cable using 10 electrodes.  The Isolated/Defibrillation Protected ECG and General Purpose Probes is able to provide a single ECG presentation.

 

Multi-Lead ECG Pod Systems include:

Isolated/Defibrillation Protected ECG and General Purpose Probes Systems include:

There are a large number of publications on the use of jacketed external telemetry, implantable telemetry, or hardwired systems to collect functional cardiovascular data.  The following publications provide rationale for adding or improving functional cardiovascular data collection in repeat dose studies.

 

  • Brian R. Berridge, Peter Hoffmann, James R. Turk, Frank Sellke, Gary Gintant, Gerald Hirkaler, Kevin Dreher, A. Eric Schultze, Dana Walker, Nick Edmunds, Wendy Halpern, James Falls, Marty Sanders, Syril D. Pettit, Integrated and translational nonclinical in vivo cardiovascular risk assessment: Gaps and opportunities, Regulatory Toxicology and Pharmacology, Volume 65, Issue 1, February 2013, Pages 38-46, doi:10.1016/j.yrtph.2012.09.007.

 

  • R. Dustan Sarazan, Scott Mittelstadt, Brian Guth, John Koerner, Joanne Zhang, and Syril Pettit, Cardiovascular Function in Nonclinical Drug Safety Assessment: Current Issues and Opportunities -Perspectives from the Health & Environmental Sciences Institute (HESI), International Journal of Toxicology, Volume 30, Issue 3, May 2011, Pages 272-286, doi:10.1177/1091581811398963

 

  • Dustan R. Sarazan, Syril D. Pettit, Brian R. Berridge, A HESI collaborative initiative towards a more integrated approach to cardiovascular safety assessment, Journal of Pharmacological and Toxicological Methods, Volume 62, Issue 2, September–October 2010, Pages e10-e11, doi:10.1016/j.vascn.2010.11.035.

 

  • S.D. Pettit, B. Berridge, R.D. Sarazan, A call for more integrated cardiovascular safety assessment, Journal of Pharmacological and Toxicological Methods, Volume 61, Issue 1, January–February 2010, Pages 1-2, doi:10.1016/j.vascn.2009.08.001.

 

The following websites also are an excellent resource for drug development guidelines and refining animal research.

 

 

  • The National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs),http://www.nc3rs.org.uk/