safety pharmacology, drug safety, safety pharm, core battery, toxicology

Safety Pharmacology

Global harmonization of drug safety testing began in the 1990s with the formation of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).  The ICH has published a number of guidelines used to test the safety of new drug candidates around the world.  Safety Pharmacology studies require cardiovascular, respiratory, and central nervous system endpoints to be collected.

In vivo, in vitro and/or ex vivo evaluations, including methods for repolarization and conductance abnormalities, may be considered.  For in vivo studies, unrestrained methods in conscious animals are preferred.

When appropriate many organizations have begun to combine Safety Pharmacology studies with traditional Toxicology studies to increase the number of valuable endpoints and reduce costs; this is achieved by spending more on the Toxicology Studies, while reducing or eliminating the Safety Pharmacology studies in the drug development process.

DSI has a long history of providing the essential tools to measure required endpoints in both Safety Pharmacology and Toxicology studies, including GLP-compliant systems for acquisition and reporting.


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Cardiovascular System

The S7A guideline requires the effects of all drug candidates on blood pressure, heart rate, and the electrocardiogram to be evaluated.  Additionally, if warranted, further evaluation of the following endpoints may need to be studied including cardiac output, ventricular contractility, vascular resistance, the effects of endogenous and/or exogenous substances on the cardiovascular responses.

When conducting in vivo studies, the guidelines prefer use of unanesthetized animals. “Data from unrestrained animals that may be chronically instrumented for telemetry, other suitable instrumentation methods for conscious animals, or animals conditioned to the laboratory environment are preferable to data from restrained or unconditioned animals.”1

Safety pharmacology studies require the use of non-rodent species, most often primates or canines, as rats do not possess the hERG (IKr) channel.  Therefore, researchers are unable to study the potential effects of a drug which may cause QT-I prolongation.

DSI solutions allow for continuous measurement of cardiovascular endpoints such as blood pressure, ECG, heart rate and more.  Analysis of these endpoints can provide common biomarker information including, but not limited to, contractility, heart rate variability, and arrhythmia.


Respiratory System

The S7A guideline also requires measurements of pulmonary function.  Follow up studies may be required if adverse effects raise concern for human safety.

Respiratory toxicology studies are performed on pharmaceuticals or chemicals when inhalation is the primary route of exposure or when the airways are the focus of interest.

Most studies are performed in rodents; rats being the primary choice. When warranted, other species are considered. Although respiratory rate and tidal volume are the typical endpoints desired, many additional derived parameters and supplemental pulmonary function measurements are available.

DSI solutions help assess the impact of compound and their potential side effects on major organ systems.

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Central Nervous System

Finally, the S7A guideline requires evaluation of the drug’s effect on the central nervous system including effects on motor activity, behavioral changes, coordination, sensory/motor reflex responses and body temperature. These are typically evaluated in rodents using the Irwin Test (or modified Irwin Test) and/or Functional Observational Battery (FOB).

The Irwin Test asses parameters including, but not limited to, death, convulsions, changes in coordination and balance, aggression, fear, analgesia, and reflexes.  Within the Harvard Bioscience family, several products are available to assist with these assessments including analgesia meters, paw volume tests, spontaneous pain tests, thermal tests, mechanical tests, automatic and manual foot misplacement tests, and rota rod.

In addition, Harvard Bioscience offers products to assist in FOB assessments such as the Grip Strength Meter which is used to screen for neurobehavioral toxicity.

Although not part of the core battery requirements, follow up studies may be considered to evaluate sleep and seizure liability.  These studies may utilize video-EEG on rodents or large animals to identify spontaneous seizure events or assess the burden of sleep and sleep disruptions resulting from the test compound.  These studies may use implantable telemetry or hardwired systems to measure EEG.

DSI solutions allow researchers to measure biopotentials of interest such as EEG, EMG, and EOG as well as body temperature, and locomotor activity.  Video monitoring can also be integrated to monitor animals throughout a study.



Implantable Telemetry
DSI offers a comprehensive line of telemetry implants capable of measuring pressure, biopotential, and respiratory endpoints as well as temperature and locomotor activity in species ranging from mice to swine.


Learn more about the pressure sensing implants available from DSI.



External Telemetry
External telemetry can be used to collect continuous data from freely moving animals when more invasive methods requiring surgery are not possible or available. In large animals, Jacketed External Telemetry (JET) can collect ECG, blood pressure, respiration, temperature and activity permitting combined safety pharmacology and toxicology studies. In small animals, the CA-EXT device can collect ECG.

Learn more about DSI's external telemetry.

Jacketed External Telemetry from DSI



Hardwired Solutions

DSI’s hardwired solutions provide a minimally invasive method to offer continuous measurement (EEG, EMG, EOG, etc.) during central nervous system studies with small animals. Hardwired solutions allow the use of a tether to monitor up to 12 EEG/EMG channels.    

A setup would include use of electrodes, wires, and commutators. EEG and/or EMG signals from this tethered approach are brought into DSI’s Ponemah software platform by the use of digital signal conditioners/amplifiers.

Learn more about Signal Conditioners and accessory PODS from DSI.

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Whole Body Plethysmography (WBP)
When conscious, unrestrained approaches are desired, FinePointe WBP allows for respiratory endpoints to be obtained. With the use of a bias flow supply, longer data collection periods can be obtained; allowing for evaluation of compounds that might have an effect beyond 4-6 hours post dose.

Learn more about FinePointe WBP products.

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Head-Out Plethysmography
Using Allay restraints, animals are comfortably and properly secured in plethysmographs without compromising the thorax to obtain consistent and reliable direct flow measurements. 

Learn more about head-out plethysmography products from DSI.

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Resistance and Compliance (RC)
FinePointe RC hardware helps researchers measure an animal’s airflow and lung pressure. This anesthetized approach allows for direct measurement pulmonary function as a follow up study to the core battery requirements.

Learn more about FinePointe RC hardware.

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Non-invasive Airway Mechanics (NAM)
Conscious follow up studies for safety pharmacology and longitudinal toxicology studies alike can take advantage of the FinePointe NAM station. Using specially designed Allay restraint and double chamber plethysmography, nasal and thoracic flow can be monitored simultaneously to derived specific airway resistance.

Learn more about FinePointe NAM products.

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Ponemah

Ponemah software is trusted by safety pharmacologists around the world to reliably and accurately acquire and analyze physiologic endpoints.

Learn more about Ponemah software from DSI.

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NeuroScore Software
After data acquisition has taken place, DSI’s NeuroScore™ software can be used to efficiently analyze chronic data sets common to neuroscience studies. This modular platform offers sleep scoring, seizure detection, video synchronization, and batch processing capabilities. 

Learn more about NeuroScore software from DSI.

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FinePointe Software
FinePointe software is powerful and easy-to-use for collecting, analyzing, and reporting life science data. Fully network-enabled, the smart design minimizes required user interaction while wizards walk users through necessary procedures.

Learn more about Buxco FinePointe software from DSI.

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References
1Guidance for Industry - S7A Safety Pharmacology: 

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm074959.pdf.%22

2Science Direct: Irwin Test: https://www.sciencedirect.com/topics/immunology-and-microbiology/irwin-test


Safety Pharmacology Society Website: http://www.safetypharmacology.org/about_sps.asp
International Council for Harmonisation website: http://www.ich.org/home.html
Society of Toxicology Website: http://www.toxicology.org/