Falcoz C, Horton J, Mackie A E, Harding S M, Daley-Yates P T
Clinical Pharmacology, Glaxo Wellcome Research and Development, Greenford, Middlesex, England.
Clin Pharmacokinet. 2000;39 Suppl 1:31-7. doi: 10.2165/00003088-200039001-00005.
The aim of these studies was to compare the pharmacokinetics of inhaled fluticasone propionate (FP) after repeated administration via the Diskus or Diskhaler dry powder inhalers (DPIs) to patients with mild-to-moderate asthma.
Both studies evaluated the pharmacokinetics of inhaled administration of FP via a DPI to patients with mild-to-moderate asthma, according to a randomised, double-blind, placebo-controlled design. In the first study, FP 100 microg or 500 microg was administered twice daily via the Diskhaler for 6 weeks and, in the second, FP 500 microg was administered via the Diskus or Diskhaler for 12 weeks.
In the first study, plasma FP concentrations could be detected consistently only with the higher dose; the lower dose produced concentrations close to or below the 0.025 microg/L quantification limit of the radioimmunoassay used. From detailed analysis of a subgroup of patients receiving the 500 microg dosage, steady-state plasma FP concentrations were attained within one week of commencing treatment. After 4 weeks, the maximum plasma FP concentration (Cmax) in this subgroup was 0.096 microg/L [95% confidence interval (CI) 0.066-0.141] and the area under the plasma FP concentration-time curve up to the last quantifiable concentration (AUClast) was 0.491 microg/L x h (95% CI: 0.256-0.940). The steady-state to single dose accumulation ratio for FP after twice-daily administration varied between patients: a ratio of approximately 1.7 was recorded after comparison of Cmax at week 4 and day 1. In the second study, the point estimate of the Diskus to Diskhaler ratio for Cmax in all patients was 0.91 (90% CI: 0.76-1.10) after 4 weeks' treatment. From a detailed analysis of a subgroup of patients, the corresponding ratio for AUClast at the same time point was 1.15 (90% CI: 0.69-1.94), indicating no significant difference in systemic exposure to FP between the 2 devices. Steady-state kinetics were achieved by week 1: the point estimate ratios of Cmax and AUClast at week 4 compared with week 1 were 0.88 (90% CI: 0.66-1.16) and 0.95 (90% CI: 0.66-1.36), respectively. Administration of FP via either DPI had no effect on plasma cortisol levels over the 12-hour postdose period.
In patients with asthma receiving repeated inhaled doses of FP, the systemic exposure (AUC) after inhalation from the Diskus was similar to that from the Diskhaler, with no difference between the DPIs in the effects on cortisol suppression. The 2 DPIs therefore have very similar pharmacokinetic profiles.
这些研究的目的是比较中度至重度哮喘患者通过都保或准纳器干粉吸入器（DPI）重复给药后吸入丙酸氟替卡松（FP）的药代动力学。
两项研究均根据随机、双盲、安慰剂对照设计，评估了中度至重度哮喘患者通过DPI吸入FP的药代动力学。在第一项研究中，通过准纳器每天两次给予100μg或500μg的FP，持续6周；在第二项研究中，通过都保或准纳器给予500μg的FP，持续12周。
在第一项研究中，仅较高剂量能持续检测到血浆FP浓度；较低剂量产生的浓度接近或低于所用放射免疫分析的0.025μg/L定量限。通过对接受500μg剂量的患者亚组的详细分析，在开始治疗的一周内达到稳态血浆FP浓度。4周后，该亚组的最大血浆FP浓度（Cmax）为0.096μg/L[95%置信区间（CI）0.066 - 0.141]，直至最后可定量浓度的血浆FP浓度 - 时间曲线下面积（AUClast）为0.491μg/L·h（95%CI：0.256 - 0.940）。每日两次给药后FP的稳态与单剂量累积比在患者之间有所不同：在比较第4周和第1天的Cmax后，记录到的比值约为1.7。在第二项研究中，治疗4周后，所有患者中都保与准纳器Cmax比值的点估计值为0.91（90%CI：0.76 - 1.10）。通过对患者亚组的详细分析，同一时间点AUClast的相应比值为1.15（90%CI：0.69 - 1.94），表明两种装置之间FP的全身暴露无显著差异。到第1周时达到稳态动力学：第4周与第1周相比，Cmax和AUClast的点估计比值分别为0.88（90%CI：0.66 - 1.16）和0.95（90%CI：0.66 - 1.36）。通过任何一种DPI给予FP在给药后12小时内对血浆皮质醇水平均无影响。
在接受重复吸入剂量FP的哮喘患者中，通过都保吸入后的全身暴露（AUC）与通过准纳器吸入后的相似，两种DPI对皮质醇抑制作用无差异。因此，这两种DPI具有非常相似的药代动力学特征。
