Effects of short-acting bronchodilators added to maintenance tiotropium therapy.

BACKGROUND: Combining bronchodilators has been shown to be beneficial in patients with COPD. The additive effects of short-acting bronchodilators added to maintenance tiotropium therapy, however, are unknown. METHODS: Following 3 weeks of tiotropium pretreatment, 60 patients with COPD (FEV1 40% of predicted) participated in a randomized, placebo-controlled study to assess add-on bronchodilator effects of ipratropium bromide (40 microg) or fenoterol (200 microg). Short-acting bronchodilators were added as a single dose 2 h and 8 h after tiotropium dosing. Serial lung function tests were performed over 9 h. RESULTS: The peak FEV1 add-on response within 6 h with fenoterol was significantly greater than with placebo (137 mL) or ipratropium (84 mL); the response with ipratropium was slightly but significantly larger than with placebo (52 mL). One hour after the second dose of the test drugs, a similar order of treatment responses was found. The peak FVC add-on response was significant for fenoterol (249 mL) but not for ipratropium (42 mL). CONCLUSIONS: In conclusion, both short-acting bronchodilator classes were effective when added to maintenance treatment with tiotropium. The addition of the beta2-adrenergic fenoterol provided greater additional bronchodilatation than the short-acting anticholinergic ipratropium. This is consistent with the expected effects of combining bronchodilators with different pharmacologic mechanisms. This randomized controlled trial was registered at www.clinicaltrials.gov (NCT00274066).

Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD.

BACKGROUND: The combination of short-acting beta(2)-agonists and anticholinergics in the treatment of COPD has been well documented, but data on combination of long-acting agents are lacking. METHODS: A randomized, open-label, placebo-controlled, three-way crossover study was conducted comparing 2-week treatment periods of tiotropium alone to tiotropium plus formoterol once or twice daily following a 2-week pretreatment period with tiotropium. Lung function (FEV(1), FVC, and resting inspiratory capacity [IC]) serially over 24 h was measured in 95 patients with stable COPD at baseline and after 2 weeks of each treatment. RESULTS: Mean baseline FEV(1) was 1.05 L (38% of predicted). There was a circadian variation in FEV(1), FVC, and IC at baseline that was maintained during all treatment periods. Average FEV(1) (0 to 24 h) improved by 0.08 L with tiotropium, by 0.16 L with tiotropium plus formoterol once daily, and by 0.20 L with tiotropium plus formoterol twice daily (p < 0.01 for all comparisons). Compared with tiotropium alone, add-on formoterol in the morning produced improvement in FEV(1), FVC, and IC for > 12 h. The second add-on dose of formoterol in the evening caused further improvement in FEV(1) for 12 h, but in FVC and IC for < 12 h. Peak increase in FEV(1) was 0.23 L (22% of baseline) with tiotropium and 0.39 L (37% of baseline) with tiotropium plus formoterol (p < 0.0001). Compared with tiotropium alone, add-on formoterol once and twice daily reduced the use of rescue salbutamol during the daytime (p < 0.01) and with add-on formoterol twice daily also during the nighttime (p < 0.05). The combination of tiotropium and formoterol was well tolerated. CONCLUSION: In the treatment of COPD, there is benefit from adding formoterol once or twice daily to tiotropium once daily in terms of improvement in airflow obstruction, resting hyperinflation, and the use of rescue salbutamol.

Pharmacodynamics and Pharmacokinetics Following Once-Daily and Twice-Daily Dosing of Tiotropium Respimat® in Asthma Using Standardized Sample-Contamination Avoidance.

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.

Once-daily tiotropium Respimat(®) 5 µg is an efficacious 24-h bronchodilator in adults with symptomatic asthma.

INTRODUCTION: Once-daily tiotropium Respimat(®) 5 µg is an efficacious add-on therapy to inhaled corticosteroids (ICS) with or without long-acting ß2-agonists in patients with symptomatic asthma. The objective of this study was to investigate whether the dosing regimen of tiotropium (once- versus twice-daily), delivered via the Respimat(®) SoftMist™ inhaler, affected 24-h bronchodilator efficacy and safety versus placebo Respimat(®) in patients with asthma who were symptomatic despite medium-dose ICS therapy. METHODS: A randomised, double-blind, placebo-controlled, crossover study with 4-week treatment periods of tiotropium 5 µg (once-daily, evening) and 2.5 µg (twice-daily, morning and evening). The primary efficacy end point was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 24 h (AUC)(0-24h) at the end of each treatment period. Secondary end points included peak forced expiratory volume in 1 s measured within 24 h of the last evening inhalation (peak FEV1(0-24h)), trough FEV1 measured prior to evening dosing, morning and evening peak expiratory flow (PEFam and PEFpm) and pharmacokinetic assessments. RESULTS: 94 patients were randomised (mean age 44.3 years; mean asthma duration 21.3 years) and 89 (94.7%) completed the study. Significant and comparable bronchodilation was achieved over a 24-h period with both tiotropium dosing regimens. FEV1 AUC(0-24h) response (mean ± standard error) was significantly greater with both tiotropium dosing regimens (once-daily 5 µg: 158 ± 24 mL; twice-daily 2.5 µg; 149 ± 24 mL; both p < 0.01) when compared with placebo. Improvements in peak FEV1(0-24h), trough FEV1 and pre-dose PEFam/pm with both dosing regimens versus placebo were statistically significant (all p < 0.01), with no statistically significant differences between the tiotropium treatment regimens. Total systemic exposure and tolerability were comparable between treatment regimens. CONCLUSIONS: Lung function improvements with tiotropium Respimat(®) add-on to medium-dose ICS were sustained and similar for once-daily 5 µg and twice-daily 2.5 µg, supporting tiotropium Respimat(®) 5 µg as a once-daily bronchodilator that provides efficacy over the whole 24-h dosing interval in patients with symptomatic asthma. ClinicalTrials.gov identifier: NCT01152450.

In Vitro, Pharmacokinetic, Pharmacodynamic, and Safety Comparisons of Single and Combined Administration of Tiotropium and Salmeterol in COPD Patients Using Different Dry Powder Inhalers.

In vitro Andersen cascade impactor-sized mass (ISM) and aerodynamic fine particle mass (FPM) <5 µm for tiotropium and salmeterol combined in a novel inhalation powder formulation containing 7.5 µg tiotropium/25 µg salmeterol (TSHH) were similar (within ±15%) to reference products containing 18 µg of tiotropium (Spiriva® HandiHaler®) (TioHH) and 50 µg of salmeterol (Serevent® Diskus®) (SalD). The pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of the novel fixed-dose TSHH formulation administered once daily was compared with the single-agent therapies TioHH (once daily [qd]) and SalD (twice daily [bid]) and with the jointly administered combination of TioHH (qd) plus SalD (bid) in a randomized, 22-week, open-label, four-way crossover study in 50 patients with chronic obstructive pulmonary disease (COPD). For tiotropium, TSHH and TioHH were bioequivalent based on mean steady-state plasma area under the plasma concentration-time curves (AUC), while the urinary excretion amount was higher for TSHH and not bioequivalent to TioHH. Tiotropium peak plasma concentrations at steady state (C max,ss) were 40% higher with TSHH. For salmeterol, substantial differences were observed in plasma AUCs and Cmax,ss. No significant differences in 8-h forced expiratory volume in 1 s or forced vital capacity were detected for the TSHH (qd) against the combination of TioHH (qd) with SalD (bid). Maintenance therapy with tiotropium plus salmeterol as TSHH or as the jointly administered reference products is superior to either agent alone, safe, and well tolerated in COPD patients. In vitro results were not predictive of clinical PK findings for both tiotropium and salmeterol for the TSHH dry powder inhaler product.