Tiotropium Respimat inhaler and the risk of death in COPD.

BACKGROUND: Tiotropium delivered at a dose of 5 µg with the Respimat inhaler showed efficacy similar to that of 18 µg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo. METHODS: In this randomized, double-blind, parallel-group trial involving 17,135 patients with COPD, we evaluated the safety and efficacy of tiotropium Respimat at a once-daily dose of 2.5 µg or 5 µg, as compared with tiotropium HandiHaler at a once-daily dose of 18 µg. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 µg or 2.5 µg vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 µg vs. HandiHaler). We also assessed cardiovascular safety, including safety in patients with stable cardiac disease. RESULTS: During a mean follow-up of 2.3 years, Respimat was noninferior to HandiHaler with respect to the risk of death (Respimat at a dose of 5 µg vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval [CI], 0.84 to 1.09; Respimat at a dose of 2.5 µg vs. HandiHaler: hazard ratio, 1.00; 95% CI, 0.87 to 1.14) and not superior to HandiHaler with respect to the risk of the first exacerbation (Respimat at a dose of 5 µg vs. HandiHaler: hazard ratio, 0.98; 95% CI, 0.93 to 1.03). Causes of death and incidences of major cardiovascular adverse events were similar in the three groups. CONCLUSIONS: 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.).

The Tiotropium Safety and Performance in Respimat Trial (TIOSPIR), a large scale, randomized, controlled, parallel-group trial-design and rationale.

BACKGROUND: Tiotropium 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. METHODS: The 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. RESULTS: To date, over 17,000 participants have been randomized from over 1200 sites in 50 countries with an anticipated treatment duration of 2-3 years. CONCLUSION: TIOSPIR 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.

Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin.

AIMS: This study examined the effects of the CYP3A/P-glycoprotein inducer, rifampicin, on the pharmacokinetics of dabigatran following oral administration of the prodrug, dabigatran etexilate. METHODS: This 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. RESULTS: Twenty-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 (AUC(0-∞)) and maximal plasma concentration (C(max)) 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 AUC(0-∞) and 34.5% (90% confidence interval 26.9, 44.1%) for C(max), 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 AUC(0-∞) and C(max) 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. CONCLUSIONS: Administration of rifampicin for 7 days resulted in a significant reduction in the bioavailability of dabigatran, which returned almost to baseline after 7 days washout.

Population in vitro-in vivo correlation model for pramipexole slow-release oral formulations.

PURPOSE: To establish an in vitro-in vivo level A correlation (IVIVC) for pramipexole slow-release formulations. METHODS: The IVIVC was developed based on data from an immediate-release (IR) and three slow-release (SR) formulations of pramipexole; a fourth SR formulation was used for validation purposes. In vitro dissolution profiles were obtained from all SR formulations. Fifteen volunteers received all pramipexole formulations in a randomized cross-over trial. Data were analyzed using the population modelling approach as implemented in NONMEM VI. RESULTS: Dissolution profiles of the SR formulations were described by the Weibull model. The pharmacokinetics of the IR formulation were described by a two-compartment disposition model with first-order absorption. Difference between the in vivo and in vitro estimates of the release rate constants (k(d)) from the Weibull function suggests the release process occurs faster in vivo. Pharmacokinetic profiles for SR formulations were described based on the in vitro release model with k(d) increased in 0.058 h(-1) and the population pharmacokinetic model developed from the IR formulation. CONCLUSION: A level A IVIVC was established and evaluated for the pramipexole SR formulations, which can be used in the future as a surrogate to avoid certain bioequivalence studies.

Pharmacokinetic and safety evaluation of BILR 355, a second-generation nonnucleoside reverse transcriptase inhibitor, in healthy volunteers.

BILR 355 is a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) under clinical development for the treatment of human immunodeficiency virus infection, particularly in those who harbor virus resistant to the currently available NNRTIs. Two single-center, double-blinded, placebo-controlled, parallel dose-escalation studies were conducted to evaluate the pharmacokinetics and safety of oral BILR 355 administration alone and after coadministration with ritonavir (RTV) at 100 mg. Following a single dose of BILR 355 in oral solution, the mean half life (t(1/2)) was 2 to 4 h, with peak concentrations occurring at 0.5 to 1 h postadministration. The mean apparent clearance (CL/F) ranged from 79.2 to 246 liters/h for administered doses of 12.5 mg to 100 mg. This observed nonlinearity in CL/F resulted from the increased bioavailability attributed to a saturated absorption and/or elimination process at higher doses. In contrast, after the coadministration of single doses of 5 mg to 87.5 mg of BILR 355 with RTV, the mean CL/F ranged from 5.88 to 8.47 liters/h. Over the dose range (5 to 87.5 mg) studied, systemic BILR 355 exposures were approximately proportional to the doses administered when they were coadministered with RTV. With RTV coadministration, the mean t(1/2) increased to 10 to 16 h, and the mean time of the maximum concentration in plasma lengthened to 1.5 to 5 h. Compared to the values for BILR 355 given alone, the mean area under the concentration-time curve from time zero to infinity, the maximum concentration in plasma, and the t(1/2) of BILR 355 achieved after coadministration with RTV increased 15- to 30-fold, 2- to 5-fold, and 3- to 5-fold, respectively. In both studies, BILR 355 appeared to be safe and well tolerated in healthy volunteers when the outcomes in the treated volunteers were compared with those in the placebo group.