Local Tolerance Studies
For many new formulations and compounds it is not only important to investigate toxicity following systemic exposure but also to investigate whether the compound give rise to local toxicity, this can be done in local tolerance studies.
At Scantox we have experience with topical application of oral patches and thin films placed either on the buccal surface or sublingual, further we also have experience with ocular administered compounds.
It may also be necessary to investigate the local tolerance following parenteral administration such as intravenous, intramuscular, subcutaneous or intraperitoneal.
In the cases where a compound is already on the market and only the formulation is altered, it is sufficient to perform a local tolerance study, possibly in combination with a kinetic study. For new compounds the situation is another; here general toxicity studies are required.
Kinetic study and profile
Kinetic studies evaluate the local tolerance at the application site. The systemic exposure will be assessed by investigating the kinetic profile of the compound.
Based on this, it will be determined if the new formulation give rise to a similar systemic exposure as the former formulation and if potential local reactions are reduced or absent.
Local tolerance studies not only apply for compounds administered by dermal application but also to a variety of other topical dosing routes.
Minipigs in local tolerance studies
For several of the administration routes the minipig has proven to be an excellent model to study local tolerance.
With decades of experience, Scantox has developed an unrivalled experience in administration of dermal formulations to minipigs ranging from very small to large volumes, ensuring the model is clinically relevant and that there will be no cross contamination.
Furthermore, we are specialized in performing local tolerance studies to ensure a long daily exposure as well as multiple daily dosing if necessary.
The size of a minipig makes it an optimal species when screening different dermal formulation candidates. By using small test sites, several formulations or concentrations can be tested in the same animal in local tolerance studies. Once the drug candidate has been selected, the different concentrations of the formulation can be tested on larger areas in separate animals allowing for e.g. inclusion of blood and/or tissue collection for kinetic profiling.
Hamster and rabbit in tolerance testing
Other species used for local tolerance testing are hamsters and rabbits. The hamsters are often the preferred choice when testing for local tolerance at the mucous membrane (cheek pouch testing).
For other products, the size of the hamster is less ideal, and a better choice is to use either dogs or minipigs to assess the local tolerance orally.
Rabbits are used when testing on very sensitive skin is relevant. Furthermore, rabbits are often used when testing local tolerance following “unintended route of dosing”. For this specific test, a single intravenous, perivenous and intra-arterial dose can easily be performed in a rabbit.
Lymph node Assay (LLNA)
For skin sensitization tests, the OECD 429 has been in place for a number of years: Skin sensitization test using the Local Lymph node Assay (LLNA).