Challenges for inhaled drug discovery and development: Induced alveolar macrophage responses

Abstract

Alveolar macrophage (AM) responses are commonly induced in inhalation toxicology studies, typically being observed as an increase in number or a vacuolated 'foamy' morphology. Discriminating between adaptive AM responses and adverse events during nonclinical and clinical development is a major scientific challenge. When measuring and interpreting induced AM responses, an understanding of macrophage biology is essential; this includes 'sub-types' of AMs with different roles in health and disease and mechanisms of induction/resolution of AM responses to inhalation of pharmaceutical aerosols. In this context, emerging assay techniques, the utility of toxicokinetics and the requirement for new biomarkers are considered. Risk assessment for nonclinical toxicology findings and their translation to effects in humans is discussed from a scientific and regulatory perspective. At present, when apparently adaptive macrophage-only responses to inhaled investigational products are observed in nonclinical studies, this poses a challenge for risk assessment and an improved understanding of induced AM responses to inhaled pharmaceuticals is required.

Insights on animal models to investigate inhalation therapy: Relevance for biotherapeutics

“…Related to the phenomenon of lung overload in rats, is the effect of poorly soluble drug particles on alveolar macrophage populations. It is has been reported that focal macrophage accumulations often with a "foamy" appearance are a frequent observation in non-clinical toxicology studies of dry powder formulations not only in rats, but non-rodent species as well (Forbes et al, 2014;Lewis et al, 2014). Above certain particle burdens, a progressive neutrophilic inflammation will develop with infiltration of inflammatory cells and elevated pro-inflammatory cytokine production.…”

In Vitro Testing for Orally Inhaled Products: Developments in Science-Based Regulatory Approaches

“…A significant portion of a poorly water soluble inhaled drug is cleared from the central lung by the mucociliary escalator, resulting in a reduced pulmonary bioavailability (27). In the peripheral regions of the lung, clearance by alveolar macrophages dominates, although insoluble particles in the lower airways can give rise to adaptive reversible alveolar macrophage responses, or at higher doses, irreversible alveolar macrophage related adverse events (57). The interplay between dissolution and permeability in the lungs is not well understood, particularly in central regions where low permeation of compounds with low water solubility could result in non-sink conditions for dissolution, making permeation through epithelium the rate-limiting step.…”

Lung inflammation does not affect the clearance kinetics of lipid nanocapsules following pulmonary administration

“…The aerosol administration of relatively insoluble compounds can result in a dose-dependent, solubilitydependent accumulation of particulate drug material in the lungs [4]. The long-term implications of macrophage responses to drugs of this nature is not completely understood and can be a barrier to the progress of such compounds to clinical development [5]. There are a variety of formulation strategies that may help circumvent the issues of insoluble particle accumulation in the airways, including the loading of agents in lipid nanocapsules [6].…”