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.

Trial registration: ClinicalTrials.gov NCT01222533.

Keywords: COPD; pharmacodynamics; pharmacokinetics; tiotropium HandiHaler®; tiotropium Respimat® SMI.

Figure 1

Flow diagram, design, and patient disposition. A total of 210 patients were initially enrolled and screened. Following a 1-week run-in period, 154 patients were randomized to five treatment groups, for a 4-week period. The number of patients in each treatment group that comprised the treatment set (TS) and the pharmacokinetic set (PS) at randomization and study end is indicated. The number of patients in each treatment group who prematurely discontinued treatment, reported any adverse event (AE) or serious AE is also indicated in the figure. The result showed that tiotropium delivered either as a powder or solution was well tolerated.

Figure 2

Clinical study. (A) Geometric mean tiotropium plasma concentration–time profile following multiple inhalations as solution or as powder. (B) Comparison of maximum tiotropium plasma concentrations at steady state (C_max,ss) by dose and device (solution versus powder). On day 26 of each treatment period, blood samples were collected 5 minutes before dosing and during a 6-hour period at 2, 5, 7, 9, 12, 15, 20, 30, 40, 60 minutes, and 2, 4, and 6 hours postdosing. Tiotropium concentrations were determined by a validated assay using high-performance liquid chromatography coupled to tandem mass spectrometry. (A) Mean plasma concentrations were (slightly) lower with tiotropium solution 5 µg compared with tiotropium powder 18 µg. (B) There was a dose-dependent increase in tiotropium plasma exposure as determined by C_max.

Figure 3

Adjusted mean FEV₁ over 6 hours at day 28. On day 28 of each treatment period, 2 days after the pharmacokinetic (PK) test day, serial 6-hour spirometry was conducted at 10 minutes before and at 30 and 60 minutes, and 2, 3, 4, 5, and 6 hours after inhalation of study medication. Tiotropium solution doses 1.25, 2.5, and 5 µg and tiotropium powder 18 µg provided significantly (P < .0001) greater bronchodilation compared to placebo in all spirometric end points. Within the first hour postdosing, tiotropium solution 2.5 µg provided less bronchodilatory effects compared with both solution 5 µg and powder 18 µg, while solution 5 µg and powder 18 µg were similar. FEV₁, forced expiratory volume in 1 second.