Toxicology Solutions

toxicology-test

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.

 

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.

 

There are multiple advantages to 24-hour continuous monitoring in repeat dose toxicology studies, the first being the ability to collect 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.

 

Another major advantage is the ability to monitor both structural and functional endpoints in the same study, allowing for the possibility to eliminate the need for a separate safety pharmacology study.  This is particularly beneficial in cardiovascular risk assessments for drug development and the development of new biological entities.  In cardiovascular risk assessment, an increasing demand from pharmaceutical companies and regulatory bodies to understand pathogenesis, structural changes, and functional changes is leading to an increase in combined safety pharmacology and toxicology studies.  The parallel dose study design required in the development of new biologics makes combining structural and functional endpoints logical.

 

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.

 

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, neurological and respiratory endpoints, are most commonly achieved using Jacketed External Telemetry (JET™), Implantable Telemetry, or Hardwired Instrumentation.

 

In 2014, DSI released the PhysioTel Digital M series telemetry implants.  These devices were designed for toxicologists seeking lower cost implants for use in studies with shorter duration and/or more test subjects. Importantly, researchers have found no histopathology issues following study completion.

 

Until recently, many toxicologists believed that the surgical implantation of sensors and telemetry devices would cause pathology that would confound the toxicologic pathology endpoints being evaluated in the study.  However, consultation with experienced pathologists participating in the HESI Cardiac Safety Technical Committee has largely removed this concern.  Pathologists are confident that they can easily distinguish pathology related to implanted foreign bodies from the pathological effects of experimental drugs.

 

In 2014, DSI also acquired Buxco Respiratory Systems, increasing our breadth of respiratory solutions for toxicology researchers, including inhalation towers, smoke generators, and whole body plethysmography chambers.

 

 

Physiologic Parameters Available for DSI Toxicology Solutions

Available
Solutions
Methods
Telemetry Hardwired
Implantable External
Blood Pressure x x x
ECG x x x
Other Biopotentials (EMG, EEG, etc.) x x
Ventricular Pressure x x
Pulse Wave Velocity x x
Blood Flow x x
Heart Rate Variability x x x
PV Loop x
Action Potentials x
Isolated Heart/Tissue x
Respiratory Rate x x x
Tidal Volume x x x
Minute Volume x x x


  

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.

 

  

 

Jacketed External Telemetry

JET is an externally-worn Bluetooth® enabled telemetry device designed for large animal toxicology studies.  JET can be used to monitor ECG, blood pressure, respiration, temperature and activity.

 

 

 

 

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.

 

 

  

 

DSI Respiratory Solutions

Please see the respiratory solutions page for detailed information on DSI's respiratory offering.

 

 

Implantable Telemetry

DSI offers two large animal implantable telemetry systems suitable for use in repeat dose toxicology studies.  The PhysioTel Digital System is the most advanced large animal telemetry system offering group-housing capability. 

 

PhysioTel Digital Systems include:

Jacketed External Telemetry

JET 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.

  • J. S. Cordes, J. R. Heyen, M. L. Volberg, N. Poy, S. Kreuser, A. M. Shoieb, J. Steidl-Nichols. (2016.) Validation and utility of the PhysioTel Digital M11 telemetry implant for cardiovascular data evaluation in cynomolgus monkeys and Beagle dogs. Journal of Pharmacological and Toxicological Methods, doi: 10.1016/j.vascn.2016.01.006
  • 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.
  • M. O. Niehoff, B. Niggemann, J. Sternberg, A. Jenkins, M. Holbrook. Measurement of hyper- and hypotension during repeat dose toxicity studies in either freely moving or physically restrained cynomolgus monkeys. Journal of Pharmacological and Toxicological Methods, Volume 70, Issue 3, September 2014, Pages 268-75, doi: 10.1016/j.vascn.2014.09.004.

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/