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

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

Author information

1
Academy of Pharmaceutical Sciences of Great Britain, UK; King's College London, Institute of Pharmaceutical Science, London SE1 9NH, UK.
2
Health and Environmental Sciences Institute, USA.
3
GlaxoSmithKline R & D, Gunnels Wood Road, Stevenage SG1 2NY, UK.
4
Amgen, USA.
5
Pfizer R & D, USA.
6
King's College London, Institute of Pharmaceutical Science, London SE1 9NH, UK.
7
Imperial College London, UK.
8
AstraZeneca R & D, Mereside, Alderley Park, Macclesfield SK10 4TG, UK.
9
GlaxoSmithKline R & D, USA.
10
SciLucent LLC, 585 Grove Street, Herndon, VA 20170, USA.
11
Seventh Wave Laboratories, USA.
12
Lovelace Respiratory Research Institute, USA.
13
AstraZeneca R & D, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
14
Novartis Horsham Research Centre, Horsham RH12 5AB, UK.

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

PMID:
24530633
DOI:
10.1016/j.addr.2014.02.001
[Indexed for MEDLINE]
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