Meibohm B, Hochhaus G, Möllmann H, Barth J, Wagner M, Krieg M, Stöckmann R, Derendorf H
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville 32610, USA.
J Pharmacokinet Biopharm. 1999 Apr;27(2):127-47. doi: 10.1023/a:1020670421957.
The suppression of endogenous cortisol release is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. The circadian rhythm of the endogenous cortisol release and the resulting plasma concentrations as well as the release suppression during corticosteroid therapy could previously be described with an integrated PK/PD model. Based on this model, a PK/PD approach was developed to quantify and predict the cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. The presented method was applied to predict CCS after single doses and during short-term multiple dosing of the inhaled corticosteroids flunisolide (FLU), fluticasone propionate (FP), and triamcinolone acetonide (TCA), and after oral methylprednisolone as systemic reference therapy. Drug-specific PK and PD parameters were obtained from previous single-dose studies and extrapolated to the multiple-dose situation. For single dosing, a similar CCS within the range of 16-21% was predicted for FP 250 micrograms, FLU 500 micrograms, and TCA 1000 micrograms. For multiple dosing, a respective CCS of 28-33% was calculated for FLU 500 micrograms bid, FP 250 micrograms, bid, and TCA 1000 micrograms bid. Higher cortisol suppression compared to these single and multiple dosing regimens of the inhaled corticosteroids was predicted after oral doses of only 1 mg and 2 mg methylprednisolone, respectively. The predictive power of the approach was evaluated by comparing the PK/PD-based simulations with data reported previously in clinical studies. The predicted CCS values were in good correlation with the clinically observed results. Hence, the presented PK/PD approach allows valid predictions of CCS for single and short-term multiple dosing of inhaled corticosteroids and facilitates comparisons between different dosing regimens and steroids.
内源性皮质醇释放的抑制是吸入性糖皮质激素治疗哮喘的主要全身性副作用之一。内源性皮质醇释放的昼夜节律及其所导致的血浆浓度，以及糖皮质激素治疗期间的释放抑制，此前可用一个整合的药代动力学/药效学（PK/PD）模型来描述。基于该模型，开发了一种PK/PD方法，以量化和预测累积皮质醇抑制（CCS），作为吸入性糖皮质激素治疗全身性活性的替代标志物。所提出的方法用于预测吸入性糖皮质激素氟尼缩松（FLU）、丙酸氟替卡松（FP）和曲安奈德（TCA）单剂量给药后以及短期多次给药后的CCS，以及口服甲泼尼龙作为全身对照治疗后的CCS。药物特异性的PK和PD参数从先前的单剂量研究中获得，并外推至多次给药情况。对于单剂量给药，预测250微克FP、500微克FLU和1000微克TCA的CCS在16 - 21%范围内。对于多次给药，计算出500微克FLU每日两次、250微克FP每日两次和1000微克TCA每日两次的相应CCS分别为28 - 33%。分别口服仅1毫克和2毫克甲泼尼龙后，预测的皮质醇抑制高于这些吸入性糖皮质激素的单剂量和多次给药方案。通过将基于PK/PD的模拟结果与先前临床研究报告的数据进行比较，评估了该方法的预测能力。预测的CCS值与临床观察结果具有良好的相关性。因此，所提出的PK/PD方法能够有效预测吸入性糖皮质激素单剂量和短期多次给药后的CCS，并有助于比较不同给药方案和糖皮质激素之间的差异。
