title: 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.
authors: Academy of Pharmaceutical Sciences of Great Britain, UK; King's College London, Institute of Pharmaceutical Science, London SE1 9NH, UK.
authors: Ben
authors: B
authors: Forbes
authors: Health and Environmental Sciences Institute, USA.
authors: Raegan
authors: R
authors: O'Lone
authors: GlaxoSmithKline R & D, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors: Philippa Pribul
authors: PP
authors: Allen
authors: GlaxoSmithKline R & D, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors: Anthony
authors: A
authors: Cahn
authors: Amgen, USA.
authors: Chris
authors: C
authors: Clarke
authors: Pfizer R & D, USA.
authors: Mark
authors: M
authors: Collinge
authors: King's College London, Institute of Pharmaceutical Science, London SE1 9NH, UK.
authors: Lea Ann
authors: LA
authors: Dailey
authors: Imperial College London, UK.
authors: Louise E
authors: LE
authors: Donnelly
authors: Pfizer R & D, USA.
authors: Joseph
authors: J
authors: Dybowski
authors: GlaxoSmithKline R & D, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors: David
authors: D
authors: Hassall
authors: GlaxoSmithKline R & D, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors: Deon
authors: D
authors: Hildebrand
authors: Pfizer R & D, USA.
authors: Rhys
authors: R
authors: Jones
authors: AstraZeneca R & D, Mereside, Alderley Park, Macclesfield SK10 4TG, UK.
authors: Joanne
authors: J
authors: Kilgour
authors: GlaxoSmithKline R & D, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors: Jan
authors: J
authors: Klapwijk
authors: GlaxoSmithKline R & D, USA.
authors: Curtis C
authors: CC
authors: Maier
authors: SciLucent LLC, 585 Grove Street, Herndon, VA 20170, USA.
authors: Tim
authors: T
authors: McGovern
authors: Seventh Wave Laboratories, USA.
authors: Kristen
authors: K
authors: Nikula
authors: GlaxoSmithKline R & D, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors: Joel D
authors: JD
authors: Parry
authors: Lovelace Respiratory Research Institute, USA.
authors: Matthew D
authors: MD
authors: Reed
authors: AstraZeneca R & D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors: Ian
authors: I
authors: Robinson
authors: Pfizer R & D, USA.
authors: Lindsay
authors: L
authors: Tomlinson
authors: Novartis Horsham Research Centre, Horsham RH12 5AB, UK.
authors: Alison
authors: A
authors: Wolfreys
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016503:Drug Delivery Systems; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control; D006801:Humans; D016676:Macrophages, Alveolar / Q000378:metabolism*; D018570:Risk Assessment / Q000379:methods; D018675:Toxicity Tests / Q000379:methods
chemical_list: D000336:Aerosols; D015415:Biomarkers
keywords: Drug delivery; Inhalation; Nonclinical; Regulatory toxicology; Respiratory; Safety