Tiotropium Respimat at a dose of 5 μg or 2.5 μg had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 μg in patients with COPD. (Funded by Boehringer Ingelheim; TIOSPIR ClinicalTrials.gov number, NCT01126437.).

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Dabigatran etexilate is an oral prodrug that is rapidly converted to dabigatran, a direct and reversible thrombin inhibitor.• Dabigatran etexilate and dabigatran are not metabolized by the cytochrome P450 system, and dabigatran does not affect the metabolism of other drugs that utilize this system, leading to a low potential for drug-drug interactions.• Dabigatran etexilate, but not dabigatran, is a P-glycoprotein (P-gp) substrate, and the bioavailability of dabigatran may be altered by P-gp inhibitors or inducers. WHAT THIS STUDY ADDS• Administration of rifampicin (a strong P-gp inducer) for 7 days before a single dose of dabigatran etexilate resulted in a significant reduction in the bioavailability of dabigatran compared with administration of dabigatran etexilate alone.• Within 7 days following the cessation of rifampicin administration, the bioavailability of dabigatran returned almost to baseline values.• Rifampicin is not recommended for use with dabigatran etexilate because of the potential for reduced systemic exposure to dabigatran. AIMSThis study examined the effects of the CYP3A/P-glycoprotein inducer, rifampicin, on the pharmacokinetics of dabigatran following oral administration of the prodrug, dabigatran etexilate. METHODSThis was an open-label, fixed-sequence, four-period study in healthy volunteers. Subjects received a single dose of dabigatran etexilate 150 mg on day 1, rifampicin 600 mg once daily on days 2-8, and single doses of dabigatran etexilate on days 9, 16 and 23. RESULTSTwenty-four subjects were treated, of whom 22 received all treatments. Relative to the reference (single dose of dabigatran etexilate alone; treatment A), administration of dabigatran etexilate following 7 days of rifampicin (treatment B) decreased the geometric mean (gMean) area under the concentration-time curve (AUC0-•) and maximal plasma concentration (Cmax) of total dabigatran by 67 and 65.5%, respectively. The time to peak and the terminal half-life were not affected. The gMean ratio for the primary comparison (treatment B vs. treatment A) was 33.0% (90% confidence interval 26.5, 41.2%) for AUC0-• and 34.5% (90% confidence interval 26.9, 44.1%) for Cmax, indicating a significant effect on total dabigatran exposure (total pharmacologically active dabigatran represents the sum of nonconjugated dabigatran and dabigatran glucuronide). After a 7 day (treatment C) or 14 day washout (treatment D), the AUC0-• and Cmax of dabigatran were reduced by 18 and 20%, and by 15 and 20%, respectively, compared with treatment A, which was considered not clinically relevant. The overall safety profile of all treatments was good. CONCLUSIONSAdministration of rifampicin for 7 days resulted in a significant reduction in the bioavailability of dabigatran, which returned almost to baseline after 7 days washout.

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BackgroundTiotropium bromide is an effective therapy for COPD patients. Comparing across programs tiotropium Respimat® Soft Mist™ inhaler was at least as efficacious as tiotropium HandiHaler®, however, concerns have been raised about tiotropium’s safety when given via Respimat®.MethodsThe TIOSPIR® trial (NCT01126437) compares the safety and efficacy of tiotropium Respimat® 5 μg once daily (marketed) and 2.5 μg once daily (investigational) with tiotropium HandiHaler® 18 μ once daily (marketed). The hypotheses to be tested are 1). that tiotropium Respimat® 5 μg once daily and Respimat® 2.5 μg once daily are non-inferior to HandiHaler® in terms of all-cause mortality, and 2). that tiotropium Respimat® 5 μg once daily is superior to HandiHaler® in terms of time to first exacerbation. A spirometry substudy evaluates the bronchodilator efficacy. The trial is a randomized, double-blind, double dummy, event-driven, parallel group study. Participants can use any background treatment for COPD except inhaled anticholinergic agents. The study encompasses a wide range of COPD patients, e.g. patients with stable cardiac diseases including arrhythmia can be included. Clinical sites are international and include both primary care as well as specialists.ResultsTo date, over 17,000 participants have been randomized from over 1200 sites in 50 countries with an anticipated treatment duration of 2–3 years.ConclusionTIOSPIR® will provide precise estimates of the relative safety and efficacy of the Respimat® and HandiHaler® formulations of tiotropium, assess potential dose-dependence of important outcomes and provide information on the clinical epidemiology of COPD in a large international patient cohort.

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