Vick Andrew, Wolff Ronald, Koester Alan, Reams Rachel, Deaver Daniel R, Heidel Shawn
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
J Aerosol Med. 2007 Summer;20(2):112-26. doi: 10.1089/jam.2007.0586.
The purpose of this study was to characterize the toxicity, pharmacokinetics, and pharmacodynamics of human insulin inhalation powder (HIIP) in beagle dogs when administered daily as an aerosolized dry powder formulation for 26 weeks via head-only inhalation. Conscious beagle dogs were exposed for 15 mins/day to an air control, placebo, maximal placebo (approximately three-fold the placebo dose), or one of three doses of HIIP (mean inhaled doses of 80, 240, or 701 microg/kg/day for the HIIP-low, HIIP-mid, and HIIP-high dose, respectively), The mass median aerodynamic diameters (MMAD) were between 2 and 3 microm and geometric standard deviation (GSD) values were approximately 2 across the groups, which is the ideal size range for favorable lung deposition. All groups were comprised of four dogs/sex, with the air control, HIIP-high, and maximal placebo groups having an additional two dogs/sex as recovery subgroups. Concentrations of serum insulin and glucose were determined from blood samples obtained following the first and last exposure for evaluation of the pharmacokinetics and pharmacodynamics of HIIP. Dose-related exposure (C(max), AUC) to inhaled insulin was observed with rapid absorption and no apparent gender differences or accumulation after repeated inhalation exposures for 26 weeks. The expected pharmacological effect of insulin was observed with dose-related decreases in serum glucose levels following HIIP administration. There were no toxic effects observed including no HIIP or placebo treatment-related effects on mean body weights, absolute body weight changes, clinical observations, food consumption, respiratory function parameters, ophthalmic examinations, electrocardiograms, heart rates, clinical pathology, or urinalysis. Similarly, there were no HIIP or placebo treatment-related effects on pulmonary assessments that included respiratory function parameters, bronchial alveolar lavage assessments, organ weights, or macroscopic and microscopic evaluations, including lung cell proliferation indices. HIIP was considered to have either low or no immunogenic potential in dogs. The no-observed-adverse-effect level (NOAEL) and maximum tolerated dose were the average inhaled dose of 701 microg insulin/kg/day.
本研究的目的是通过仅头部吸入的方式，以雾化干粉制剂形式每日给药26周，来表征人胰岛素吸入粉（HIIP）在比格犬中的毒性、药代动力学和药效学。清醒的比格犬每天暴露于空气对照组、安慰剂组、最大安慰剂组（约为安慰剂剂量的三倍）或三种剂量的HIIP之一（HIIP低剂量、HIIP中剂量和HIIP高剂量组的平均吸入剂量分别为80、240或701μg/kg/天）15分钟。各组的质量中值空气动力学直径（MMAD）在2至3微米之间，几何标准差（GSD）值约为2，这是有利于肺部沉积的理想粒径范围。所有组每组有四只不同性别的犬，空气对照组、HIIP高剂量组和最大安慰剂组每组额外有两只不同性别的犬作为恢复亚组。在首次和末次暴露后采集血样，测定血清胰岛素和葡萄糖浓度，以评估HIIP的药代动力学和药效学。观察到吸入胰岛素的剂量相关暴露（C(max)，AUC），吸收迅速，重复吸入暴露26周后无明显性别差异或蓄积。给予HIIP后，观察到血清葡萄糖水平呈剂量相关下降，出现了胰岛素预期的药理作用。未观察到毒性作用，包括HIIP或安慰剂治疗对平均体重、绝对体重变化、临床观察、食物消耗、呼吸功能参数、眼科检查、心电图、心率、临床病理学或尿液分析均无相关影响。同样，HIIP或安慰剂治疗对肺部评估（包括呼吸功能参数、支气管肺泡灌洗评估、器官重量或宏观和微观评估，包括肺细胞增殖指数）均无相关影响。HIIP被认为在犬中具有低免疫原性或无免疫原性。未观察到不良反应水平（NOAEL）和最大耐受剂量为平均吸入剂量701μg胰岛素/kg/天。
