Regulatory toxicology considerations for the development of inhaled pharmaceuticals

Abstract

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.

Foamy macrophage responses in the rat lung following exposure to inhaled pharmaceuticals: a simple, pragmatic approach for inhaled drug development

“…Despite enormous amounts of resource and investment (not to mention optimism), success stories in the field of inhaled drugs are largely limited to these three main target classes: β 2 ‐adrenergic receptor agonists, muscarinic antagonists and corticosteroids (Forbes et al ., ; Owen, ; Yeadon, ). In addition to the lack of clinical efficacy of many new drug candidates, one of the main problems encountered, and a significant source of attrition during the development of new inhaled drugs, is the induction of foamy macrophage responses, particularly in rats.…”

“…In addition to the lack of clinical efficacy of many new drug candidates, one of the main problems encountered, and a significant source of attrition during the development of new inhaled drugs, is the induction of foamy macrophage responses, particularly in rats. As such, this issue has been provoking considerable debate within the inhaled drug development community (Forbes et al ., ; Jones and Neef, ; Owen, ).…”

“…One of the main reasons for the increase in foamy macrophage responses is the desire to develop inhaled drugs of low solubility to avoid systemic absorption and to prolong intrapulmonary activity (Byron, ; Casarosa et al ., ; Forbes et al ., ; Jones and Neef, ; Owen, ). A major role of alveolar macrophages is the phagocytosis and clearance of inhaled particulates, preventing damage to the delicate and highly functional alveolar epithelium.…”

“…Thus, in preclinical studies, a predictable consequence of inhalation exposure to poorly soluble drugs has been the development of foamy macrophage responses at the site of major particle deposition, i.e. the bronchioloalveolar junctions, especially in rats (Forbes et al ., ; Jones and Neef, ; Lewis and McKevitt, ; Owen, ). It is unclear whether phagocytosed particles of poorly soluble, slowly dissolving drugs such as fluticasone propionate are subsequently able to egress from the cell (Patton and Byron, ).…”

“…The potential for these macrophage responses to exacerbate pre‐existing pulmonary conditions in humans, and an inability to monitor these changes in clinical trials, has led to concern from regulatory agencies, notably the US Food and Drug Administration, and in some cases to drugs being placed on clinical hold (Owen, ). As is often the case in drug development, there is a paucity of published findings (Forbes et al ., ; Jones and Neef, ; Owen, ) and consequently there is little guidance on the interpretation of toxicity studies, particularly with poorly soluble inhaled drugs (Jones and Neef, ).…”