Sharma Ashish, Kerstjens Huib A M, Aalbers René, Moroni-Zentgraf Petra, Weber Benjamin, Dahl Ronald
Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, Biberach 88400, Germany.
University of Groningen, Department of Pulmonology, and Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
Pulm Pharmacol Ther. 2017 Feb;42:25-32. doi: 10.1016/j.pupt.2016.12.003. Epub 2016 Dec 28.
Tiotropium is a long-acting inhaled antimuscarinic bronchodilator that has recently received marketing authorization for the indication of asthma with dose delivery via the Respimat inhaler, in addition to its widely established role in the management of chronic obstructive pulmonary disease (COPD). This report presents a combined analysis of tiotropium plasma and urine pharmacokinetics at steady state from 8 Phase II/III clinical trials in asthma and delineates the effects of patient characteristics on systemic exposure based on the parameters fe (fraction of dose excreted unchanged in urine over 24 h post-dose at steady-state) and dose-normalized AUC and C. Pharmacokinetics were also compared between asthma and COPD, incorporating data from 3 COPD Phase II/III clinical trials. Tiotropium pharmacokinetics in asthma were dose-proportional up to 5 μg dosed once daily. The following factors showed no statistically significant effects on tiotropium systemic exposure in asthma based on analysis of geometric mean ratios and 90% confidence intervals: age, asthma severity, lung function, reversibility testing, allergy status, smoking history, geographical region, and posology (5 μg once daily or 2.5 μg twice daily via Respimat). Asian patients showed a moderately but significantly higher systemic exposure compared to White or Black patients. However, no differences in safety by race were observed. Total systemic exposure (AUC) was similar between asthma and COPD, but C was 52% lower in asthma patients compared to COPD. It is concluded that in asthma, patient characteristics have no relevant effect on tiotropium systemic exposure. Since systemic exposure to inhaled drugs is an indicator of safety, the lower C compared to COPD is not considered a concern for tiotropium therapy of asthma.
噻托溴铵是一种长效吸入性抗毒蕈碱支气管扩张剂，除了在慢性阻塞性肺疾病（COPD）管理中已确立的广泛作用外，最近还获得了通过Respimat吸入器给药用于哮喘适应症的上市许可。本报告对哮喘8项II/III期临床试验中噻托溴铵稳态时的血浆和尿液药代动力学进行了综合分析，并根据参数fe（稳态给药后24小时尿液中以原形排泄的剂量分数）以及剂量标准化的AUC和C，描述了患者特征对全身暴露的影响。还比较了哮喘和COPD之间的药代动力学，纳入了3项COPD II/III期临床试验的数据。哮喘患者中，噻托溴铵的药代动力学在每日一次给药剂量高达5μg时呈剂量正比关系。基于几何平均比值和90%置信区间的分析，以下因素对哮喘患者中噻托溴铵的全身暴露无统计学显著影响：年龄、哮喘严重程度、肺功能、可逆性测试、过敏状态、吸烟史、地理区域和给药方案（通过Respimat每日一次5μg或每日两次2.5μg）。与白人或黑人患者相比，亚洲患者的全身暴露略高但显著更高。然而，未观察到种族间安全性的差异。哮喘和COPD之间的总全身暴露（AUC）相似，但哮喘患者的C比COPD患者低52%。得出的结论是，在哮喘中，患者特征对噻托溴铵的全身暴露无相关影响。由于吸入药物的全身暴露是安全性的一个指标，与COPD相比，C较低不被认为是噻托溴铵治疗哮喘的一个问题。
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