title: Pharmacokinetics of tiotropium administered by Respimat®in asthma patients: Analysis of pooled data from Phase II and III clinical trials.
abstract: 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 fe0-24,ss(fraction of dose excreted unchanged in urine over 24 h post-dose at steady-state) and dose-normalized AUCtau,ssand Cmax,ss. 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 (AUCtau,ss) was similar between asthma and COPD, but Cmax,sswas 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 Cmax,sscompared to COPD is not considered a concern for tiotropium therapy of asthma.
authors.affiliation: Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, Biberach 88400, Germany. Electronic address: Ashish.Sharma@boehringer-ingelheim.com.
authors.forename: Ashish
authors.initials: A
authors.lastname: Sharma
authors.affiliation: 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.
authors.forename: Huib A M
authors.initials: HA
authors.lastname: Kerstjens
authors.affiliation: Department of Pulmonary Diseases, Martini Hospital, Groningen, 9700 RM, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Aalbers
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Strasse 173, Ingelheim 55216, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Moroni-Zentgraf
authors.affiliation: Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, Biberach 88400, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weber
authors.affiliation: Department of Clinical Medicine - Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Ronald
authors.initials: R
authors.lastname: Dahl
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D001249:Asthma / Q000188:drug therapy*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D016032:Randomized Controlled Trials as Topic; D000069447:Tiotropium Bromide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D001993:Bronchodilator Agents; D000069447:Tiotropium Bromide
keywords: Asthma; Pharmacokinetics; Respimat(®) inhaler; Tiotropium