Investigation of Lung Pharmacokinetic of the Novel PDE4 Inhibitor CHF6001 in Preclinical Models: Evaluation of the PreciseInhale Technology
Investigation of Lung Pharmacokinetic of the Novel PDE4 Inhibitor CHF6001 in Preclinical Models: Evaluation of the PreciseInhale Technology
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DOI：
10.1089/jamp.2017.1369
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发表时间：
2018-02-01
影响因子：
3.4
通讯作者：
Puccini, Paola
中科院分区：
文献类型：
--
作者：
Fioni, Alessandro;Selg, Ewa;Puccini, Paola
背景：临床前评估新化学实体（NCEs）设计通过吸入途径给药需要对啮齿动物进行肺给药，特别是在发现阶段。到目前为止，已经使用了不同的给药方法，但是当只有少量整齐的粉末材料可用时，需要更多的努力来获得可控制和可重复的肺沉积。方法：在本研究中使用的precise吸气平台可以很好地控制粉末气溶胶暴露，只有少量的微粉化的整洁材料，在非常早期的阶段提供NCEs的吸入药代动力学（PK）数据。“尘埃枪”气溶胶技术使用压缩空气，从毫克级的粉末中产生可呼吸的气溶胶，每次给一只动物注射。采用新方法，在precise吸气平台的三种暴露模型（纯鼻、气管内插管大鼠和离体、通气和灌注大鼠肺）中研究了新型Chiesi PDE4抑制剂CHF6001的吸入PK和肺潴留。结果与临床前研究中常用的另外两种肺输送系统（液体注入和粉末注入）的数据进行了比较。结果：使用precise吸气系统给药的微细化CHF6001的肺暴露范围与其他测试设备相同，但肺沉积的重现性得到了改善。在第一个采样时间点，肺中CHF6001的初始量接近预定目标剂量。precise吸气的气管沉积（0.360.22g）明显少于其他测试的输送系统：PennCentury （23.7 +/- 3.2g）和Airjet （25.6 +/- 7.2g）。结论：precise吸气平台使CHF6001粉末给药具有良好的准确性和重复性，且气管沉积低。新平台可以在早期发现阶段使用，以获得不含辅料的纯NCE粉末可吸入气溶胶的吸入PK数据，并且最少使用干粉配方工作。
Background: Preclinical evaluation of new chemical entities (NCEs) designed to be administered by inhalation route requires lung administration to rodents, especially in the discovery phase. Different administration methods have been used until now, but more efforts are required to obtain controlled and reproducible lung deposition when only small amounts of neat powder material are available. Methods: The PreciseInhale platform used in the present study enables well-controlled powder aerosol exposures with only small amounts of micronized neat material, providing data on inhalation pharmacokinetic (PK) of NCEs at a very early stage. The DustGun aerosol technology uses compressed air to generate a respirable aerosol from milligram-amounts of powder that is delivered to one animal at a time. The new methodology was used to investigate the inhalation PK and lung retention in the rat of the novel Chiesi PDE4 inhibitor CHF6001 in three exposure models of the PreciseInhale platform: nose-only, intratracheally intubated rat, and the isolated, ventilated, and perfused rat lung. Results were compared with data from two other pulmonary delivery systems commonly used in preclinical studies: liquid instillation and powder insufflation. Results: Administration of micronized CHF6001 using the PreciseInhale system yielded lung exposures in the same range as the other tested devices, but the reproducibility in lung deposition was improved. The initial amount of CHF6001 in lungs at the first sampling time point was close to the predetermined target dose. Tracheal deposition with PreciseInhale (0.360.22g) was significantly less than with other tested delivery systems: PennCentury (23.7 +/- 3.2g) and Airjet (25.6 +/- 7.2g). Conclusions: The PreciseInhale platform enabled the administration of CHF6001 powder with good accuracy and reproducibility, with low tracheal deposition. The new platform can be used at an early discovery stage to obtain inhalatory PK data for respirable aerosols of neat NCE powder without excipients and with minimal use of dry powder formulation work.