Category: Nonclinical Safety Assessment; Study Design
Safety Phamacology: Core Battery Reloaded
By Roman Goetz
According to the ICH Harmonized Tripartite Guideline: Safety Pharmacology Studies for Human Pharmaceuticals (ICH S7A guideline), safety pharmacology studies are purposed to investigate potential undesirable pharmacodynamic effects of a substance on physiological
functions in relation to exposure in the therapeutic range and above(ICH, 2000). The core battery of safety pharmacology studies includes evaluation of the central nervous system (CNS), respiratory system, and cardiovascular (CV) function.
Rodents have been established as standard for evaluation of the CNS and respiratory function,and large animal species are the standard for CV assessment. Here, we are primarily discussing the options of evaluating CNS and respiratory
function in large animals if rodents are not relevant at all for testing of a specific therapeutic modality. Moreover, we also take a look at options to integrate the evaluation of safety pharmacology parameters into general toxicology studies.
Guideline provides flexibility for species selection
According to the ICH S7A guideline, there is no firm requirement on species to use in the safety pharmacology core battery testing; the guideline rather states that “consideration should be given to the selection of relevant animal models
or other test systems so that scientifically valid information can be derived. […] Justification should be provided for the selection of the particular animal model or test system.”
For some products, rodents do not represent relevant species for assessment of safety and toxicity. Therefore, the question arises on evaluating safety pharmacology in large animals only. A few possibilities and models are being offered,
which are briefly discussed in the following. Such alternative approaches are advised to be discussed on a case-by-case basis with respective contract research organizations (CROs) and ultimately with the regulatory agencies.
Alternative approaches for respiratory and CNS evaluation in non-rodents
Assessment of respiratory function may be combined with CV evaluation. Respiratory inductance plethysmography (RIP) is an available technique that is being offered for example for monkeys, dogs and minipigs. This system allows for comparison
of thoracic and abdominal breathing. From this measurement, parameters like respiratory rate, tidal volume and minute volume can be deducted.
Assessment of neurological/neurobehavioral parameters and reflexes may also be included into a CV safety pharmacology study. For that purpose, a separate dosing session is added for evaluation of neurobehavioral parametersvia species-tailored
functional observational battery (FOB). This combined setup is for example available in monkeys and dogs. As with a standard CV (telemetry) setup, test item should be properly washed out between the sessions.
It goes without saying that assessment of CNS or respiratory function in large animals, as described above, may also be set up as stand-alone study.
Conversely, there are also experimental settings of evaluating CV parameters in rodents, such as measurement of blood pressure by implanted devices, or even electrocardiography(ECG) upon implantation of subcutaneous electrodes.
Thinking of 3Rs- Integrating endpoints into general toxicology studies
Though outside the box of discussing stand-alone safety pharmacology studies, we are now taking a look to integrating safety pharmacology assessment into general toxicology (specifically, repeat dose toxicity) studies. For example, assessment
of CV safety pharmacology may be integrated into general toxicology studies in large animals. In such add-on setup, an implant may be used for determination of blood pressure, while a jacketed system (jacketed external telemetry(JET)) is used
for ECG. Full implantation may be perceived as possibly interfering with normal toxicology endpoints. However, fully implantable technology for acquiring ECG, blood pressure and body temperature is on the way to replace jacketed systems.
Assessment of respiratory function (via RIP, as discussed above) may also be an add-on to a repeat dose toxicity study in large animals.
Evaluation of safety pharmacology parametersshould normally not be done upon the first dosing occasion in a repeat dose study design, sincecollection of samples for toxicokinetic assessment (typically upon the first dose) may interfere
with assessment of CV parameters.
In remains to note that plethysmography for respiratory assessment may also be incorporated into repeatdose toxicitystudies in rodents.
The following Table 1 summarizes the possible approaches discussed above:
Concluding, there are more options for assessment of safety pharmacology than just evaluation of CNS and respiratory system in rodent and evaluation of CV function in large animals.
MC Toxicology Consulting is at your availability to select appropriate study setups and to connect with CROs that offer extended capabilities for executing non-standard approaches.
ICH, 2000. ICH Harmonized Tripartite Guideline: Safety Pharmacology Studies for Human Pharmaceuticals (S7A); November 2000.