title: Pharmacodynamics and Pharmacokinetics Following Once-Daily and Twice-Daily Dosing of Tiotropium Respimat®in Asthma Using Standardized Sample-Contamination Avoidance.
abstract: BACKGROUND
  This study was conducted to confirm the 24-hour bronchodilator efficacy and pharmacokinetic profile of once-daily tiotropium Respimat®5 μg add-on to inhaled corticosteroids (ICS) in adults with symptomatic asthma. It used a trial protocol designed to minimize the risk of pharmacokinetic sample contamination resulting from improper sampling procedure, sample handling, or device handling during priming and subsequent inhalation procedure.
  
  
  METHODS
  A Phase II, randomized, double-blind, two-way crossover study (NCT01696071) comparing two daily dosing regimens of tiotropium for 4 weeks, once-daily 5 μg (evening dosing) or twice-daily 2.5 μg (morning and evening dosing), as add-on to maintenance therapy with ICS (400-800 μg budesonide or equivalent) as controller medication. There was no washout between treatment periods.
  
  
  RESULTS
  An increase in the area under the curve of the 24-hour forced expiratory volume in 1 second profile from study baseline was observed following once-daily tiotropium 5 μg (217 mL) and twice-daily 2.5 μg (219 mL), with no difference between the two regimens (-2 mL [95% confidence interval: -38, 34]). In a subset of the study population, total tiotropium exposure, expressed as area under the plasma concentration versus time curve over 24 hours, was comparable between dosing regimens. Unexpected tiotropium plasma levels were observed in two patients, possibly because of contamination.
  
  
  CONCLUSIONS
  The observed bronchodilator efficacy over 24 hours was similar with once-daily tiotropium 5 μg and twice-daily 2.5 μg as add-on to ICS therapy, supporting the suitability of once-daily dosing to provide sustained improvements in lung function in adults with symptomatic asthma.
authors: 1 Insaf Institut für Atemwegsforschung GmbH , Wiesbaden, Germany .
authors: Kai-Michael
authors: KM
authors: Beeh
authors: 2 Pulmonary Research Institute at LungClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research , Grosshansdorf, Germany .
authors: Anne-Marie
authors: AM
authors: Kirsten
authors: 3 Pulmonary Department and Adult Cystic Fibrosis Center, Université Paris Descartes, Cochin Hospital , Paris, France .
authors: Daniel
authors: D
authors: Dusser
authors: 4 Translational Medicine and Clinical Pharmacology , Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany .
authors: Ashish
authors: A
authors: Sharma
authors: 5 TA Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG , Ingelheim am Rhein, Germany .
authors: Piet
authors: P
authors: Cornelissen
authors: 6 Global Biometrics and Data Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach an der Riss, Germany .
authors: Ralf
authors: R
authors: Sigmund
authors: 5 TA Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG , Ingelheim am Rhein, Germany .
authors: Petra
authors: P
authors: Moroni-Zentgraf
authors: 7 Allergy Centre, Odense University Hospital , Odense, Denmark .
authors: Ronald
authors: R
authors: Dahl
keywords: Respimat®; asthma; blood-sampling contamination; pharmacodynamics; pharmacokinetics; tiotropium