Inhaled Product Development, GlaxoSmithKline Research and Development, Ware, United Kingdom.
J Aerosol Med Pulm Drug Deliv. 2012 Jun;25(3):169-78. doi: 10.1089/jamp.2011.0902. Epub 2012 Jan 26.
Small rodents continue to be the mainstay for the assessment of pharmacological and toxicological data of inhaled therapeutics. For meaningful interpretation of the results information about deposition of aerosol particles in the respiratory tract is warranted, but not trivial to obtain for animals with nose-only aerosol exposure. The purpose of this study was to develop and evaluate a general method to characterize the deposition of inhaled test particles in an in vitro model (IVR) of the rat's respiratory tract.
A highly detailed, realistic and representative image using micro-CT scanning technology was obtained and the generated morphological data was used to construct a plastic replica of the average rat respiratory tract. The model was connected to a rodent ventilator, which allowed the breathing frequency (f, min(-1)) and tidal volume (V(T), mL) to be varied as required. Polydisperse fluorescent microsphere particles with an average mass median aerodynamic diameter (MMAD) of 3.1 μm and geometric standard deviation (GSD) of 2.2 μm were used as model compound.
Comparison of the experimental data for total and regional deposition levels with predicted outputs using the in silico MPPD model showed reasonably good relative agreement between the two models. The predictions were closest to the experimental values when default respiratory conditions of f=102 breaths/min and V(T) of 2.0 mL were used. Moreover, the IVR model revealed good correlation with published in vivo data.
Using the IVR model allows an easy, fast and reasonably precise estimation of the inhaled dose in rodent inhalation studies. The IVR has the potential to be used along with live rats in inhalation exposure studies, and thus provides the unique possibility to run an internal standard for dose deposition in the respiratory tract in each inhalation experiment. This should contribute to enable a greater understanding of drug pharmacokinetics and dynamics in rats and may improve dose extrapolation from animals to humans.
小型啮齿动物仍然是评估吸入治疗药物的药理学和毒理学数据的主要方法。为了对结果信息进行有意义的解释，需要了解气溶胶颗粒在呼吸道中的沉积情况，但对于仅进行鼻腔暴露的动物来说，这并不容易获得。本研究旨在开发和评估一种通用方法，以描述吸入试验颗粒在大鼠呼吸道体外模型（IVR）中的沉积情况。
使用微 CT 扫描技术获得高度详细、真实和具有代表性的图像，并使用生成的形态数据构建大鼠呼吸道平均塑料复制品。该模型与啮齿动物呼吸机连接，允许根据需要改变呼吸频率（f，min(-1))和潮气量（V(T)，mL)。使用平均质量中值空气动力学直径（MMAD）为 3.1 μm 和几何标准偏差（GSD）为 2.2 μm 的多分散荧光微球颗粒作为模型化合物。
将总沉积水平和区域沉积水平的实验数据与使用体内 MPPD 模型预测的输出进行比较，发现两种模型之间具有相当好的相对一致性。当默认呼吸条件为 f=102 次/分钟和 V(T)为 2.0 mL 时，预测值与实验值最为接近。此外，IVR 模型与已发表的体内数据具有良好的相关性。
使用 IVR 模型可以方便、快速且相当精确地估计啮齿动物吸入研究中的吸入剂量。IVR 有可能与活鼠一起用于吸入暴露研究中，从而为每个吸入实验中呼吸道内的剂量沉积提供内部标准提供了独特的可能性。这应该有助于更好地理解大鼠药物的药代动力学和动力学，并可能改善从动物到人类的剂量外推。
