title: Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease.
abstract: The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 µg, and placebo), and open-label powder 18 µg, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (Cmax,ss ), and area under the plasma concentration-time profile (AUC0-6h,ss ), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss , indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD.
authors.affiliation: Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Hannover, Germany.
authors.forename: J M
authors.initials: JM
authors.lastname: Hohlfeld
authors.forename: A
authors.initials: A
authors.lastname: Sharma
authors.forename: J A
authors.initials: JA
authors.lastname: van Noord
authors.forename: P J G
authors.initials: PJ
authors.lastname: Cornelissen
authors.forename: E
authors.initials: E
authors.lastname: Derom
authors.forename: L
authors.initials: L
authors.lastname: Towse
authors.forename: V
authors.initials: V
authors.lastname: Peterkin
authors.forename: B
authors.initials: B
authors.lastname: Disse
mesh_terms: D000368:Aged; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018680:Cholinergic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D008875:Middle Aged; D011208:Powders; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D012602:Scopolamine Derivatives / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012996:Solutions; D000069447:Tiotropium Bromide; D016896:Treatment Outcome
chemical_list: D001993:Bronchodilator Agents; D018680:Cholinergic Antagonists; D011208:Powders; D012602:Scopolamine Derivatives; D012996:Solutions; D000069447:Tiotropium Bromide
keywords: COPD; pharmacodynamics; pharmacokinetics; tiotropium HandiHaler®; tiotropium Respimat® SMI