Mackie A E, Bye A
Lilly Research Centre Limited, Windlesham, Surrey, England.
Clin Pharmacokinet. 2000;39 Suppl 1:47-54. doi: 10.2165/00003088-200039001-00007.
The aim of this analysis was to assess the pharmacokinetic/pharmacodynamic relationship between systemic exposure to fluticasone propionate (FP) and reductions in the plasma cortisol level and urinary cortisol excretion.
A total of 122 healthy male volunteers participating in 7 different studies received either oral (5 to 40 mg), inhaled (500 to 2000 microg) or intravenous (250 to 1000 g) single morning doses of FP or placebo. Data on systemic exposure to FP, expressed in terms of the area under the FP concentration-time curve up to 24 hours (AUC(24h,FP)) for the 3 different routes of administration were pooled, together with corresponding data on the 24-hour plasma cortisol level or urinary cortisol excretion. The data were used to develop a pharmacokinetic/pharmacodynamic model, from which parameter estimates and 95% confidence intervals (CI) for the estimates could be derived.
The intercept in the absence of drug (E0) was -0.5% (95% CI: -0.6, -0.3%) and the maximum drug-induced reduction in mean plasma cortisol levels (Emax) was 72% (95% CI: 64, 79%). The systemic exposure to FP that resulted in half the maximum possible reduction in plasma cortisol levels (AUC50) was 3.2 microg/L x h (95% CI: 2.8, 3.7 microg/L x h); this equates approximately to the plasma FP concentration obtained after administration of a 1000 microg inhaled dose. A similar relationship was seen between AUC50 and urinary cortisol excretion, although the variability in AUC50 for urinary cortisol was much greater than for plasma cortisol.
A pharmacokinetic/pharmacodynamic model has been established which relates systemic exposure to FP (after a single morning dose) to the percentage reduction in urinary or plasma cortisol. The relationship is independent of both dose and route of administration.
本分析旨在评估丙酸氟替卡松（FP）全身暴露量与血浆皮质醇水平降低及尿皮质醇排泄减少之间的药代动力学/药效学关系。
共有122名健康男性志愿者参与了7项不同研究，他们接受了口服（5至40毫克）、吸入（500至2000微克）或静脉注射（250至1000微克）单次早晨剂量的FP或安慰剂。汇总了3种不同给药途径下以FP浓度-时间曲线下至24小时的面积（AUC(24h,FP)）表示的FP全身暴露量数据，以及24小时血浆皮质醇水平或尿皮质醇排泄的相应数据。这些数据用于建立药代动力学/药效学模型，从中可以得出参数估计值和估计值的95%置信区间（CI）。
无药物时的截距（E0）为-0.5%（95%CI：-0.6，-0.3%），药物引起的平均血浆皮质醇水平最大降低值（Emax）为72%（95%CI：64，79%）。导致血浆皮质醇水平最大可能降低一半的FP全身暴露量（AUC50）为3.2微克/升·小时（95%CI：2.8，3.7微克/升·小时）；这大约相当于吸入1000微克剂量后获得的血浆FP浓度。AUC50与尿皮质醇排泄之间也观察到类似关系，尽管尿皮质醇的AUC50变异性远大于血浆皮质醇。
已建立了一个药代动力学/药效学模型，该模型将单次早晨剂量后FP的全身暴露量与尿或血浆皮质醇的降低百分比相关联。这种关系与剂量和给药途径均无关。
