Toxicologic Testing of Inhaled Pharmaceutical Aerosols

Abstract

This paper reviews technical issues related to the toxicologic testing of inhaled pharmaceuticals. Although there are commonalities between approaches to general and inhalation toxicity testing, there also are specific challenges in the toxicity testing of inhaled pharmaceuticals. A major issue is that of dose; inhaled dose is more difficult to determine than intravenous or oral doses. Also, it is harder to relate dose in laboratory animals to that in man for inhalation exposure than for other routes of administration. Additionally, in the case of inhaled pharmaceuticals, people generally inhale through the mouth, whereas most laboratory animals inhale primarily through the nose. This presents significant challenges in exposure methodology and technology that often need innovative approaches involving alteration to particle size of the agent or dosing procedure. Because the respiratory tract is the site of deposition, local respiratory toxicity and possible damage to lung cells need to be assessed. Systemic toxicity also needs to be evaluated and may be an issue in some cases. Special studies on pulmonary function, mucociliary clearance, or immune response may be needed, depending on the nature of the inhaled pharmaceutical. This review explores the main issues involved in toxicity testing of inhaled pharmaceuticals, the approaches that have been used, and the current and future challenges.

Inhaled Antibiotics for Gram-Negative Respiratory Infections

“…In general, testing and proving the safety of inhaled antibiotics are much more difficult than for other routes of administration in in vitro, preclinical, and clinical studies (325). In addition, current pharmaceutical toxicology studies judge safety margins based on target organ toxicity measured as a function of the drug exposure (AUC) in the organ relative to plasma.…”

The Relevance of Animal Models for Aerosol Studies

“…(26) provide statistically meaningful results. (93)(94)(95)(96) Rodents, typically rats and mice, are also used for studies relating to lethality, reproduction, teratology, motor activity, metabolism, toxicokinetics, metaplastic events, etc. (94) More advanced, and confirmatory testing is generally conducted in dogs or nonhuman primates.…”

Alternative Routes of Drug Administration—Advantages and Disadvantages (Subject Review)

“…• Drug metabolism in the respiratory tract and reduction of systemic effect 82 • Possible conversion to carcinogens 83 • Protein binding • Mucociliary transport causing increased or decreased drug residence time • Local toxic effects of the drug (eg, edema, cell injury, or altered tissue defenses) 84 • Local or systemic toxic effects of propellants, preservatives, or carriers such as sulfites 84 …”