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

Adv Drug Deliv Rev. 2014 May;71:15-33. doi: 10.1016/j.addr.2014.02.001. Epub 2014 Feb 13.

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.

Keywords: Drug delivery; Inhalation; Nonclinical; Regulatory toxicology; Respiratory; Safety.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Aerosols
  • Animals
  • Biomarkers / metabolism
  • Drug Delivery Systems*
  • Drug Design*
  • Drug Discovery / methods
  • Drug-Related Side Effects and Adverse Reactions / prevention & control
  • Humans
  • Macrophages, Alveolar / metabolism*
  • Risk Assessment / methods
  • Toxicity Tests / methods

Substances

  • Aerosols
  • Biomarkers