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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., (© 2013 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

In the past mucoactive drugs in airway diseases have been identified and profiled in symptom-based animal experiments and in clinical trials along related lines (cough and expectoration). Presently available drugs of this class are not generally accepted by licensing authorities worldwide and no new molecule clinically profiled as a mucoactive drug has been brought to regulatory approval in the past 20 years. Among regulatory guidelines only the CPMP 1999 'points to consider' on drug development in chronic obstructive pulmonary disease (COPD) advises for mucoactive drug development by suggesting that an indication for symptomatic treatment may be established on the basis of a symptom-related primary endpoint that should be justified as for its importance and supported by a co-primary lung function endpoint. Quality and safety of the new drug must be documented in long-term studies and the indication and use clearly described based on established or adequately profiled new primary endpoints in two pivotal studies. Published trials on mucoactive drugs have used a variety of endpoints. These include mucus hypersecretion-related symptoms by questionnaire, expectorated volume and dry weight, and mucus viscosity, elasticity and transportability. Most methods and endpoints are not validated and a positive standard of treatment is not established. New surrogate markers of efficacy for shorter term trials, e.g. induced or spontaneous sputum based assays (cellularity, mucus antigens), exhaled breath (NO), breath condensate (eicosanoids) or airway biopsy are only partially validated and the risk of false positive or negative phase II results is appreciably high. On the other hand, lung function measurements including airway hyper-reactivity assessment and typical phase III (long-term) endpoints like dyspnoea ratings, health status assessments, incidence of exacerbations and lung function decline over time are validated endpoints and offer a high likelihood of regulatory acceptance. Proof for no depression of lung mucociliary clearance is an important safety endpoint.