Mechanism of Action
Tiotropium is a long-acting, antimuscarinic agent, which is often referred to as an
anticholinergic. It has similar affinity to the subtypes of muscarinic receptors,
M1 to M5. In the airways, it
exhibits pharmacological effects through inhibition of M3-receptors
at the smooth muscle leading to bronchodilation. The competitive and
reversible nature of antagonism was shown with human and animal origin receptors and
isolated organ preparations. In preclinical in vitro as well as in vivo studies,
prevention of methacholine-induced bronchoconstriction effects was dose-dependent
and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium
is predominantly a site-specific effect.
Pharmacodynamics
Cardiovascular Effects
In a multicenter, randomized, double-blind trial that enrolled 198 patients with COPD,
the number of subjects with changes from baseline-corrected QT interval of 30 to 60 msec
was higher in the SPIRIVA HandiHaler group as compared with placebo. This difference was
apparent using both the Bazett (QTcB) [20 (20%) patients vs 12 (12%) patients] and
Fredericia (QTcF) [16 (16%) patients vs 1 (1%) patient] corrections of QT for heart rate.
No patients in either group had either QTcB or QTcF of >500 msec. Other clinical studies
with SPIRIVA HandiHaler did not detect an effect of the drug on QTc intervals.
The effect of SPIRIVA HandiHaler on QT interval was also evaluated in a randomized, placebo- and
positive-controlled crossover study in 53 healthy volunteers. Subjects received SPIRIVA HandiHaler
18 mcg, 54 mcg (3 times the recommended dose), or placebo for 12 days. ECG assessments were performed
at baseline and throughout the dosing interval following the first and last dose of study medication.
Relative to placebo, the maximum mean change from baseline in study-specific QTc interval was 3.2 msec
and 0.8 msec for SPIRIVA HandiHaler 18 mcg and 54 mcg, respectively. No subject showed a new onset of
QTc >500 msec or QTc changes from baseline of ≥60 msec.
Pharmacokinetics
Tiotropium is administered by dry powder inhalation. In common with other inhaled drugs, the majority
of the delivered dose is deposited in the gastrointestinal tract and, to a lesser extent, in the lung,
the intended organ. Many of the pharmacokinetic data described below were obtained with higher doses
than recommended for therapy.
Absorption
Following dry powder inhalation by young healthy volunteers, the absolute bioavailability of 19.5%
suggests that the fraction reaching the lung is highly bioavailable. It is expected from the chemical
structure of the compound (quaternary ammonium compound) that tiotropium is poorly absorbed from the
gastrointestinal tract. The effect of food on tiotropium's bioavailability has not been studied.
Oral solutions of tiotropium have an absolute bioavailability of 2% to 3%. Maximum tiotropium plasma
concentrations were observed 5 minutes after inhalation.
Distribution
Tiotropium shows a volume of distribution of 32 L/kg indicating that the drug binds extensively to
tissues. The human plasma protein binding for tiotropium is 72%. At steady state, peak tiotropium
plasma levels in COPD patients were 17 to 19 pg/mL when measured 5 minutes after dry powder
inhalation of an 18 mcg dose and decreased in a multi-compartmental manner. Steady-state trough
plasma concentrations were 3 to 4 pg/mL. Local concentrations in the lung are not known, but the
mode of administration suggests substantially higher concentrations in the lung. Studies in rats
have shown that tiotropium does not readily penetrate the blood-brain barrier.
Metabolism
The extent of metabolism appears to be small. This is evident from a urinary excretion of 74% of
unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester,
is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, neither
of which bind to muscarinic receptors.
In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction
of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25%
for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione
conjugation to a variety of Phase II metabolites. This enzymatic pathway can be inhibited by CYP450 2D6
and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved
in the metabolic pathway that is responsible for the elimination of a small part of the administered dose.
In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations
did not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.
Elimination
The terminal elimination half-life of tiotropium was between 5 and 6 days following inhalation. Total
clearance was 880 mL/min after an intravenous dose in young healthy volunteers with an inter-individual
variability of 22%. Intravenously administered tiotropium was mainly excreted unchanged in urine (74%).
After dry powder inhalation, urinary excretion was 14% of the dose, the remainder being mainly non-absorbed
drug in the gut which was eliminated via the feces. The renal clearance of tiotropium exceeds the
creatinine clearance, indicating active secretion into the urine. After chronic once-daily inhalation by
COPD patients, pharmacokinetic steady state was reached after 2 to 3 weeks with no accumulation thereafter.
Drug Interactions
An interaction study with tiotropium (14.4 mcg intravenous infusion over 15 minutes) and cimetidine 400 mg
three times daily or ranitidine 300 mg once daily was conducted. Concomitant administration of cimetidine
with tiotropium resulted in a 20% increase in the AUC0-4h, a 28% decrease in the
renal clearance of tiotropium and no significant change in the Cmax and amount
excreted in urine over 96 hours. Co-administration of tiotropium with ranitidine did not affect the
pharmacokinetics of tiotropium.
Specific Populations
Geriatric Patients
As expected for drugs predominantly excreted renally, advanced age was associated with a decrease of
tiotropium renal clearance (326 mL/min in COPD patients <58 years to 163 mL/min in COPD patients
>70 years), which may be explained by decreased renal function. Tiotropium excretion in urine
after inhalation decreased from 14% (young healthy volunteers) to about 7% (COPD patients). Plasma
concentrations were numerically increased with advancing age within COPD patients (43% increase in
AUC0-4 after dry powder inhalation), which was not significant when considered
in relation to inter- and intra-individual variability [see Dosage and Administration and Use in
Specific Populations].
Renal Impairment
Since tiotropium is predominantly renally excreted, renal impairment was associated with increased
plasma drug concentrations and reduced drug clearance after both intravenous infusion and dry powder
inhalation. Mild renal impairment (creatinine clearance of 50 to 80 mL/min), which is often seen in
elderly patients, increased tiotropium plasma concentrations (39% increase in AUC0-4
after intravenous infusion). In COPD patients with moderate to severe renal impairment (creatinine clearance
of <50 mL/min), the intravenous administration of tiotropium resulted in doubling of the plasma concentrations
(82% increase in AUC0-4), which was confirmed by plasma concentrations after dry
powder inhalation. Patients with moderate to severe renal impairment (creatinine clearance of ≤50 mL/min)
treated with SPIRIVA HandiHaler should be monitored closely for anticholinergic side effects [see Dosage
and Administration, Warnings and Precautions, and Use in Specific Populations].
Hepatic Impairment
The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.