Derendorf H, Hochhaus G, Krishnaswami S, Meibohm B, Möllmann H
Department of Pharmaceutics, College of Pharmacy, University of Florida, USA.
Pharmazie. 2000 Mar;55(3):223-7.
During recent years, the treatment of pulmonary diseases could be significantly improved due to the introduction of modern retrometabolism-based corticosteroids with improved therapeutic ratio. It is the goal of all inhaled corticosteroids to produce long lasting therapeutic effects at the pulmonary target site and to minimize systemic side effects by rapid clearance of the absorbed drug and low oral bioavailability. The development of PK/PD models allows predictions of drug effects based on the administered dose. For example, the cumulative suppression of endogenous cortisol release (CCS) as one of the major systemic side effects of inhaled corticosteroid therapy can be described with an integrated Emax based PK/PD model. In order to assess the predictive power of this model, a study was conducted to compare the PK/PD-based predictions with CCS data obtained from actual clinical trials for flunisolide, fluticasone propionate, budesonide and triamcinolone acetonide. CCS was predicted for different single doses from different inhaler devices for each drug and a good correlation was observed. Thus, the presented PK/PD model proved to be a valid tool for predicting CCS of inhaled corticosteroids. By fully understanding the underlying mechanisms it will be possible to further improve their therapeutic index.
近年来，由于引入了治疗指数更高的基于逆向代谢的现代皮质类固醇，肺部疾病的治疗得到了显著改善。所有吸入性皮质类固醇的目标都是在肺部靶位点产生持久的治疗效果，并通过快速清除吸收的药物和低口服生物利用度将全身副作用降至最低。PK/PD模型的发展使得基于给药剂量预测药物效果成为可能。例如，吸入性皮质类固醇治疗的主要全身副作用之一——内源性皮质醇释放的累积抑制（CCS），可以用一个基于Emax的综合PK/PD模型来描述。为了评估该模型的预测能力，进行了一项研究，将基于PK/PD的预测结果与从氟尼缩松（flunisolide）、丙酸氟替卡松（fluticasone propionate）、布地奈德（budesonide）和曲安奈德（triamcinolone acetonide）的实际临床试验中获得的CCS数据进行比较。对每种药物不同吸入装置的不同单剂量进行了CCS预测，观察到良好的相关性。因此，所提出的PK/PD模型被证明是预测吸入性皮质类固醇CCS的有效工具。通过充分理解其潜在机制，将有可能进一步提高它们的治疗指数。
