Regulatory toxicology considerations for the development of inhaled pharmaceuticals.

The preclinical safety studies required to support the development of inhaled drugs are generally the same as for other routes of administration. Repeat-dose toxicology studies should be conducted by inhalation to ensure the characterization of both the local (i.e., respiratory) and systemic toxicity, although some studies (e.g., reproductive) can be performed by utilizing alternative routes, when it is paramount to maximize systemic exposure. Respiratory tract changes in preclinical species can include irritancy of the larynx and nasal cavity, particularly in rodents. Such changes are not necessarily predictive of a risk to humans because of the exquisite sensitivity of the rodent larynx and the lack of exposure to the nasal cavity after oro-inhalation of drugs in the clinical setting. The design of poorly soluble molecules to limit systemic exposure places greater emphasis on the elimination of drugs from the lungs by macrophages. Consequently, an increase in macrophage numbers is often noted, and in the absence of any other changes, this is generally considered to be a nonadverse, physiological response to an inhaled particulate. Other changes in the lung, which can include an inflammatory response and/or epithelial hyperplasia, resulting from irritancy or particulate overload, are a safety concern and are not monitorable in humans. For such changes, safety margins can be calculated in terms of the drug deposited per unit weight of lung. These factors should be taken into account when designing preclinical studies or programs for inhaled drugs.