Mr. Littner et al., Long-acting bronchodilation with once-daily dosing of tiotropium (Spiriva)in stable chronic obstructive pulmonary disease, AM J R CRIT, 161(4), 2000, pp. 1136-1142
Tiotropium (Spiriva; Ba679BR) is a new-generation, long-acting anticholiner
gic bronchodilator that has muscarinic M-1 and M-3 receptor subtype selecti
vity. A multicenter, randomized, double-blind, parallel group, placebo-cont
rolled study was conducted to evaluate the dose-response characteristics of
tiotropium inhalation powder given once daily to stable patients with chro
nic obstructive pulmonary disease (COPD). Patients (mean FEV1 = 1.08 L [42%
predicted]) were randomized to receive 0, 4.5, 9, 18, or 36 mu g tiotropiu
m once daily at noon for 4 wk, with spirometry done before and hourly for 6
h after dosing. Patients measured and recorded their peak expiratory flow
rates (PEFRs) three times each day. Significant dose-related improvement in
FEV1 and significant improvement in FVC occurred within 1 h after the firs
t dose of tiotropium as compared with placebo. Over the 29 d of the study,
all doses of tiotropium produced significant increases over placebo in trou
gh (i.e, as measured spirometrically at 20 to 24 h after the previous dose
and just before the next dose of tiotropium), peak, and 6-h postdose averag
e FEV1 and FVC, and in PEFR, without a significant difference among the dif
ferent doses investigated. PEFR gradually returned to pretreatment baseline
levels over a 3-wk evaluation period following the discontinuation of tiot
ropium. The overall safety profile far the tiotropium doses was, similar to
that for placebo. In summary, tiotropium was shown to be safe and effectiv
e in doses ranging from 4.5 to 36 mu g delivered once daily. The improvemen
ts in spirometry with once-daily dosing confirm the long duration of action
of tiotropium reported in single-dose studies, and its sustained improveme
nt of spirometric measures over the 1 mo of testing in the study points to
utility of tiotropium as a maintenance bronchodilator for patients with COP
D. On the basis of the comparable bronchodilator response at doses from 9 t
o 36 mu g, and advantages suggested by the safely profile at doses below 36
mu g In this study, a dose of 18 mu g once daily was selected for use in l
ong-term studies of the safety and efficacy of tiotropium.