Mackie A E, McDowall J E, Falcoz C, Ventresca P, Bye A, Daley-Yates P T
Lilly Research Centre, Windlesham, Surrey, England.
Clin Pharmacokinet. 2000;39 Suppl 1:23-30. doi: 10.2165/00003088-200039001-00004.
The aim of these studies was to determine the absolute bioavailability in healthy volunteers of inhaled fluticasone propionate (FP) administered as a single dose via the Diskhaler and Diskus powder devices, and the pharmacokinetics of inhaled FP after repeated administration via the Diskhaler device.
In 2 of the studies, single inhaled doses of FP were administered via the Diskhaler and the Diskus powder devices, and, in the third study, repeated doses of FP were administered via the Diskhaler. In the single dose studies, 12 healthy volunteers were randomised to receive FP 1000 microg by inhalation and FP 250 microg intravenously, using a double-blind crossover design. In the repeated dose study, 24 healthy volunteers received FP 1000 microg twice daily for 7.5 days.
Systemic exposure to FP after administration of a single 1000 microg inhaled dose of FP via the 2 powder devices was similar; the area under the plasma FP concentration-time curve (AUC) to infinite time (AUCinfinity) was 2.08 microg/L x h [95% confidence intervals (CI): 1.63-2.64] for Diskhaler and 2.49 microg/L x h (95% CI: 2.09-2.96) for Diskus. Maximum plasma FP concentration (Cmax) was 0.34 microg/L for both devices. Mean bioavailability values via the Diskhaler and Diskus were 11.9% (95% CI: 9.0-15.7%) and 16.6% (95% CI: 13.6-20.3%), respectively. No clinically significant reductions in urinary cortisol excretion were recorded in these 2 studies. After repeated administration with the Diskhaler, steady state was achieved by dose 3 (i.e. day 2) onwards. After dose 15, the AUC up to 12 hours (AUC12h) was 2.25 microg/L x h and Cmax was 0.38 microg/L. The mean steady-state to single dose accumulation ratio after twice-daily administration was 1.49 (95% CI: 1.36-1.62).
The pharmacokinetics of FP administered by the 2 powder devices are similar in healthy volunteers, although systemic bioavailability was greater with the Diskus.
这些研究的目的是确定健康志愿者通过Diskhaler和Diskus干粉吸入装置单剂量吸入丙酸氟替卡松（FP）后的绝对生物利用度，以及通过Diskhaler装置重复给药后吸入FP的药代动力学。
在其中2项研究中，通过Diskhaler和Diskus干粉吸入装置单剂量吸入FP，在第3项研究中，通过Diskhaler重复给药。在单剂量研究中，12名健康志愿者采用双盲交叉设计，随机接受1000μg吸入FP和250μg静脉注射FP。在重复给药研究中，24名健康志愿者每天两次接受1000μg FP，共7.5天。
通过2种干粉装置单剂量吸入1000μg FP后，全身对FP的暴露相似；血浆FP浓度-时间曲线下面积（AUC）至无限时间（AUCinfinity），Diskhaler为2.08μg/L·h [95%置信区间（CI）：1.63 - 2.64]，Diskus为2.49μg/L·h（95% CI：2.09 - 2.96）。两种装置的最大血浆FP浓度（Cmax）均为0.34μg/L。通过Diskhaler和Diskus的平均生物利用度值分别为11.9%（95% CI：9.0 - 15.7%）和16.6%（95% CI：13.6 - 20.3%）。这2项研究中未记录到尿皮质醇排泄有临床显著降低。通过Diskhaler重复给药后，从第3剂（即第2天）起达到稳态。第15剂后，12小时内的AUC（AUC12h）为2.25μg/L·h，Cmax为0.38μg/L。每日两次给药后，平均稳态与单剂量累积比为1.49（95% CI：1.36 - 1.62）。
在健康志愿者中，2种干粉装置给药的FP药代动力学相似，尽管Diskus的全身生物利用度更高。
