By: Narayanan Rajendran
New drug development for inhaled medications or repurposing of approved drugs for inhalation delivery is on the rise due to the the increasing incidence of lung disease in the aging population. Chronic respiratory diseases are now the 3rd leading cause of death in the United States for the population 65 years and over, rising from 5th in 1980.
For drug developers, direct delivery of medications to the lungs has several advantages: delivery of the therapeutic to the site of action, reducing exposure and potential side effects; bypassing first-pass metabolism; and convenience over more invasive routes such as injection, intravenous or intramuscular.
Early preclinical studies to qualify viable drug candidates for further development include generating efficacy, pharmacokinetics (PK), and bioavailability data in animal models. The active pharmaceutical product (API) for these studies is typically sourced from non-GLP manufacturing batches. For inhalation dosing, researchers are often surprised to learn that these preclinical studies require much greater quantities of API than traditional routes (oral, IM, or IV), and their available API may fall far short of the amount needed.
The reason for this excess API requirement in inhalation dosing is twofold. Typical nose-only inhalation exposure chamber systems need a substantial amount of test article to generate the inhalation atmosphere. Then, when the animal is exposed to the atmosphere and the aerosolized drug is inhaled, only a small fraction of the inhaled dose is deposited in the lungs. For small animals (rodents), the amount of dose deposited is typically only 10% of the dose inhaled, but it can be as high as 25% for a larger animal.
To avoid delays and additional costs to manufacture more of an unproven drug, there are API-conserving techniques that can be used in early PK study dosing. Animals can be manually dosed using specialized delivery devices that deliver aerosols directly to the trachea, bypassing the nasal cavity and larynx. Test animals are anesthetized and the drug is administered through the device’s rigid tube extending into the trachea of the animal. The required quantity of API is loaded into the reservoir of the dispenser and dispersed as an aerosol plume into the lungs.
This approach allows for delivery of the drug by simulating the normal dispersion that occurs via breathing, while also conserving the amount of API used. Additionally, since the aerosol is delivered directly to the closed space of the lungs, it improves the deposition of particles and minimizes loss. However, given the need to anesthetize animals undergoing this procedure, this method is best suited for studies requiring single-dose administrat
ion or a dosing regimen with multiple days of rest in between.
Intratracheal administration of aerosols for early PK or efficacy studies mitigates the need to generate large quantities of test atmosphere and the requirement for large amounts of API. If the results of the early PK or efficacy studies are favorable, manufacturing greater quantities for investigational new drug-enabling preclinical inhalation toxicology studies are warrented.