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Niche Nonclinical Studies: Uncommon Routes of Administration and Animal Models

Premier Partners has worked on more than 200 nonclinical programs since its inception in 2005, many of which include rare routes of administrations (ROAs) and use of uncommon animal species. We have collaborated with sponsors on many niche programs that have shone a light on both the creativity and the broad range of specialized capabilities needed for such complex development programs.

Drugs are delivered to where they need to go in the human body by many routes of administration, such as through orifices (as in oral or nasal delivery) and parenteral injections (e.g., intramuscular delivery). Prior to human administration, each route of administration (ROA) must be tested in animals. Common ROAs used to perform toxicology studies include oral, intravenous, subcutaneous, inhalation, and topical delivery, but there are numerous more including intravesical, intravitreal, intrathecal, and intralymphatic.

Intravesical

Intravesical administration involves introducing a urethral catheter to deliver a drug close to its target organ: the bladder. It is often used in bladder oncology programs to directly expose the drug to cells lining the inside of the bladder while reducing any unintended systemic exposure or consequences. While there are technical difficulties associated with replicating this ROA in animals with much smaller target organs, experienced nonclinical subject-matter experts can anticipate and mitigate these issues.

Intravitreal

Intravitreal administration consists of injecting a drug product into the space between the lens and the retina of the eye, where the vitreous humor resides. Although it can sometimes cause unwanted ocular pressure, intravitreal administration remains the standard way to deliver drugs to treat many ocular and retinal diseases. In nonclinical studies, which are often conducted in rabbits, an ophthalmologist must perform the dosing.

Intrathecal

Intrathecal administration involves an injection into the space around the brain and spinal cord where the cerebrospinal fluid resides. Often used in pain management and analgesia, these drug products can be delivered via the spinal canal or the subarachnoid space. Of note, although patients and doctors appreciate the fast-acting properties of this ROA, it is a sensitive space, and the FDA has warned against off-label use of implanted pumps.

Intralymphatic

Intralymphatic administration consists of directly injecting a drug product into a subcutaneous lymph node. This ROA, known in the allergy field as intralymphatic immunotherapy, has been added to the previously existing treatment options — subcutaneous or sublingual allergen injections. Since intralymphatic injections were shown to be more efficacious, safer, faster, less painful, and more convenient, they have easily replaced both previous options as the new gold standard.

Niche nonclinical animal species

Regulatory agencies often require that preclinical toxicology studies be conducted in two mammalian species (one rodent, one non-rodent) and that the test material be pharmacologically active in the chosen species. Over the years, reagent development and accumulating baseline data have pushed the industry toward choosing rat or mouse for rodents and dog or non-human primate for non-rodents. However, there are numerous less-common options, including hamster, guinea pig, ferret, and lamb.

Hamster: The hamster is currently experiencing a rise in popularity as an animal model for SARS-CoV-2 studies, as it models the pulmonary pathology and viral load characteristic of human COVID-19 cases. This is why the Syrian hamster had been identified as having great potential for infectious-disease research even prior to the pandemic.

Guinea pig: The guinea pig is used to study infectious disease, but it is more widely used today in nutritional research because of its involvement in the discovery of vitamin C. Thanks to its strong gestational similarities with humans, it is used as an alternative species for development and reproductive toxicology (DART) studies.

Ferret: The ferret is yet another species used to study infectious disease and has also been cited as a potential animal model for SARS-CoV-2 studies. It is most known for its use in influenza virus research, as it can catch and transmit the human virus efficiently while showing human-like clinical signs including sneezing, nasal discharge, lethargy, fever, and weight loss.

Lamb: The lamb, or the adult sheep, has proven greatly useful as a model to study major physiological systems, including the respiratory system. It is also useful in DART and pregnancy studies and in studying neurodegenerative diseases. Given its large size, there are no barriers concerning frequent blood sampling or tissue collection. Instead, issues arise on the husbandry side with a somewhat prohibitive cost.

As complex products and development programs continue to grow in popularity, it is possible that niche routes of administration and less commonly used animal species will become more mainstream in the future, increasing the demand for niche program execution capabilities. With deep nonclinical expertise and experience on more than 200 nonclinical programs, Premier Consulting provides solutions to help you design, execute, and manage your complex nonclinical programs. Contact us to learn more about our experience and what we can add to your program.

Author:

Camille Delouche, MSc
Associate, Camargo Accelerator Program

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