Academy of Pharmaceutical Sciences of Great Britain, UK; King's College London, Institute of Pharmaceutical Science, London SE1 9NH, UK.
Health and Environmental Sciences Institute, USA.
Adv Drug Deliv Rev. 2014 May;71:15-33. doi: 10.1016/j.addr.2014.02.001. Epub 2014 Feb 13.
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.
肺泡巨噬细胞 (AM) 的反应通常在吸入毒理学研究中被诱导，通常表现为数量增加或出现空泡化的“泡沫状”形态。在非临床和临床开发过程中，区分适应性 AM 反应和不良事件是一个重大的科学挑战。在测量和解释诱导的 AM 反应时，对巨噬细胞生物学的理解至关重要；这包括在健康和疾病中具有不同作用的“亚型”的 AM 以及诱导/解决 AM 对吸入药物气溶胶反应的机制。在这种情况下，新兴的测定技术、毒代动力学的实用性以及对新生物标志物的需求都被考虑在内。从科学和监管的角度讨论了非临床毒理学发现的风险评估及其对人类的影响。目前，当在非临床研究中观察到明显适应吸入性研究产品的巨噬细胞反应时，这对风险评估提出了挑战，需要更好地了解吸入性药物对 AM 的诱导反应。
