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.

Keywords: Respimat®; asthma; blood-sampling contamination; pharmacodynamics; pharmacokinetics; tiotropium.

FIG. 1.

Study design. Sequence 1: tiotropium 5 μg administered once daily in the evening and placebo in the morning for 4 weeks, followed by tiotropium 2.5 μg administered in the morning and evening for 4 weeks. Sequence 2: tiotropium 2.5 μg administered twice daily for 4 weeks followed by tiotropium 5 μg administered once daily for 4 weeks. Patients (n = 98) were randomized 1:1 to sequence 1 or sequence 2. BID, twice daily; ICS, inhaled corticosteroids; QD, once daily.

FIG. 2.

Pharmacokinetic procedures and lung function testing at Visits 4 and 6. Pharmacokinetic subset (n = 35). ^aPre-dose urine sample obtained from urine collected in the last hour before study drug administration. ^bAll urine voided during the 0- to 6-hour post-dose interval. ^cAll urine voided during the 6- to 12-hour post-dose interval. ^dAll urine voided during the 12- to 24-hour post-dose interval. ^eForced expiratory volume in 1 second, forced vital capacity, and peak expiratory flow completed using the MasterScope^® CT. ^fLung function testing performed at 10:00, 11:00, 13:00, 15:00, 17:00, 18:00, and 18:50. ^gAdministration of a patient's own inhaled corticosteroids according to his/her regular dosing. PK, pharmacokinetics.

FIG. 3.

CONSORT diagram. BID, twice daily; QD, once daily.

FIG. 4.

FEV₁ response over 24 hours following the final once-daily and twice-daily doses at the end of each 4-week treatment period (full analysis set). BID, twice daily; FEV₁, forced expiratory volume in 1 second; QD, once daily.

FIG. 5.

Geometric mean tiotropium plasma concentration–time profiles following multiple inhalations to steady state of 5 μg via the Respimat^® inhaler by patients with moderate persistent asthma. PK measurements performed 15 min before evening administration, and after 2, 5, 7, 10, 15, and 30 min and 1, 3, and 11.75 h (morning administration 12 hours following the evening dose), 12 hours +2, 5, 7, 10, 15, and 30 min, and 13, 15, and 23.75 h relative to the evening dose. Pharmacokinetic subset (n = 35). BID, twice daily; QD, once daily.