Aviar Mechanism of Action

Pharmacotherapeutic group: Other drugs for obstructive airways diseases, inhalants, anticholinergics. ATC code: R03BB04.
Pharmacology: Tiotropium bromide is a long-acting, specific antimuscarinic agent, in clinical medicine often called an anticholinergic. It has a similar affinity to the subtypes of muscarinic receptors M₁ to M₅. In the airways, inhibition of M₃-receptors at the smooth muscle results in relaxation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In non-clinical in vitro as well as in vivo studies bronchoprotective effects were dose-dependent and lasted longer than 24 hours. The long duration of effect is likely to be due to its very slow dissociation from M₃-receptors, exhibiting a significantly longer dissociation half-life than that seen with ipratropium. As an N-quaternary anticholinergic Tiotropium is topically (broncho-) selective when administered by inhalation, demonstrating an acceptable therapeutic range before giving rise to systemic anticholinergic effects. Dissociation from M₂-receptors is faster than from M₃ which in functional in vitro studies, elicited (kinetically controlled) receptor subtype selectivity of M₃ and M₂.
The high potency and slow receptor dissociation found its clinical correlate in significant and long-acting bronchodilation in patients with COPD.
The bronchodilation following inhalation of Tiotropium is primarily a local effect (on the airways) not a systemic one.
Cardiac electrophysiology: In a dedicated QT study involving 53 healthy volunteers, Tiotropium bromide 10 mcg and 54 mcg (i.e. three times the therapeutic dose) over 12 days did not prolong QT intervals of the ECG.
Clinical efficacy: The clinical development program included four one-year and two six-month randomized, double-blind studies in 2663 patients with COPD (1308 receiving Tiotropium bromide). The one-year program consisted of two placebo-controlled and two ipratropium-controlled trials. The six-month trials were both salmeterol- and placebo-controlled. These studies included evaluation of lung function, dyspnea, exacerbations of COPD and patients assessments of their health-related quality of life.
Lung function: Tiotropium bromide administered once daily, provided significant improvement in lung function (forced expiratory volume in one second, FEV₁ and forced vital capacity, FVC) within 30 minutes following the first dose and was maintained for 24 hours. Pharmacodynamic steady state was reached within one week with the majority of bronchodilation observed by the third day. Tiotropium bromide significantly improved morning and evening peak expiratory flow rate (PEFR) as measured by patient's daily recordings.
The improvement in lung function with Tiotropium bromide was demonstrated throughout the period of administration in the six long-term trials. These improvements were maintained with no evidence of tolerance.
A randomized, placebo-controlled clinical study in 105 patients with COPD demonstrated that bronchodilation was maintained throughout the 24 hour dosing interval in comparison to placebo regardless of whether Tiotropium bromide was administered in the morning or in the evening.
Long-term clinical trials (6 months and 1 year): Dyspnea, Exercise tolerance: Tiotropium bromide significantly improved dyspnea (as evaluated using the Transition Dyspnea Index). This improvement was maintained throughout the treatment period.
The impact of improvement in dyspnea on functional activities was investigated in two randomized double blind placebo controlled trials in COPD patients. In these trials, Tiotropium bromide significantly improved symptom limited exercise tolerance by 19.7% and 28.3% compared with placebo.
Health-related Quality of Life: Tiotropium bromide significantly improved health-related quality of life as demonstrated by the disease-specific St. George's Respiratory Questionnaire. This improvement was maintained throughout the treatment period.
COPD Exacerbations: Tiotropium bromide significantly reduced the number of COPD exacerbations and delayed the time to first exacerbation in comparison to placebo.
Additionally, in the one year placebo controlled trials Tiotropium bromide significantly reduced the number of hospitalizations associated with COPD exacerbations and delayed the time to first hospitalization.
A one-year randomized, double-blind, double-dummy, parallel-group trial compared the effect of treatment with 18 mcg of Tiotropium bromide once daily with that 50 mcg of salmeterol HFA pMDI twice daily on the incidence of moderate and severe exacerbations in 7,376 patients with COPD and a history of exacerbation in the preceding year.
Compared with salmeterol, Tiotropium bromide increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium bromide also increased the time to the first severe (hospitalized) exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduce the annual number of moderate or severe (hospitalized) exacerbations (0.64 vs. 0.72, rate ratio 0.89; 95% CI, 0.83 to 0.96; P=0.002) and reduced the annual number of severe (hospitalized) exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001).
Long term clinical trials (>1 up to 4 years): In a 4-year trial of 5,993 patients Tiotropium bromide maintained improvements in FEV1 throughout 4 years but did not alter the annualized rate of decline of FEV1.
During treatment, there was a 16% reduction in the risk of death. The incidence rate of death was 4.79 per 100 patient years in the placebo group vs. 4.10 per 100 patient years in the Tiotropium group (hazard ratio (Tiotropium/placebo) = 0.84), 95% CI=0.73, 0.97). Treatment with Tiotropium reduced the respiratory failure by 19% (2.09 vs. 1.68 cases per 100 patient years, relative risk (Tiotropium/placebo) = 0.81, 95% CI=0.65, 1.00).
Long-term Tiotropium active-controlled study: A long term, large scale, randomized, double-blind, active-controlled study with a treatment period up to 3 years has been performed to compare the efficacy and safety of Tiotropium bromide (5,711 patients receiving Tiotropium bromide) 2.5 microgram (5 microgram medicinal dose); 5,694 patients receiving the dose. The primary endpoints were time to first COPD exacerbation, time to all-cause mortality and in a sub-study (906 patients) trough FEV1 (pre-dose).
The time to first COPD exacerbation was similar during the study with Tiotropium bromide and the Handihaler (hazard ratio (Tiotropium bromide/Handihaler)) 0.98 with a 95% CI of 0.93 to 1.03. The median number of days to the first COPD exacerbation was 756 days for Tiotropium bromide and 719 days for the device.
The bronchodilator effect of Tiotropium bromide was sustained over 120 weeks, and was similar to the device. The mean difference in trough FEV1 for Tiotropium bromide versus the Handihaler was 0.10 L (95% CI -0.038 to 0.018 mL).
All-cause mortality was similar during the study with Tiotropium bromide and Handihaler ratio (Tiotropium bromide/Handihaler) 0.96 with a 95% CI of 0.84 to 1.09.
Pharmacokinetics: Tiotropium is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium is administered by dry powder inhalation. Generally with the inhaled route of administration, the majority of the delivered dose is deposited in the gastrointestinal tract, and to a lesser extent in the intended organ of the lung. Many of the pharmacokinetic data described as follows were obtained with higher doses as 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.
Oral solutions of Tiotropium have an absolute bioavailability of 2-3%. Food is not expected to influence the absorption of Tiotropium for the same reason.
Maximum Tiotropium plasma concentrations were observed 5-7 minutes after inhalation. At steady state, peak Tiotropium plasma concentrations in COPD patients were 12.9 pg/mL and decreased rapidly in a multi-compartmental manner. Steady state trough plasma concentrations were 1.71 pg/mL.
Distribution: Tiotropium has a plasma protein binding of 72% and shows a volume of distribution of 32 L/kg. 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 penetrate the blood-brain barrier to any relevant extent.
Biotransformation: The extent of biotransformation is small. This is evident from a urinary excretion of 75% 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, both not binding to muscarinic receptors.
In vitro experiments with human liver microsomes and human hepatocytes suggest that some further drug (<20% of dose after intravenous administration) 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 the CYP450 2D6 (and 3A4) inhibitors, quinidine, ketoconazole and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a smaller part of the dose. Tiotropium bromide even in supra-therapeutic concentrations does not inhibit cytochrome P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A in human liver microsomes.
Elimination: The effective half-life of Tiotropium ranges between 27-45 h in healthy volunteers and COPD patients. Total clearance was 880 mL/min after an intravenous dose in young healthy volunteers. Intravenously administered Tiotropium bromide is mainly excreted unchanged in urine (74%). After inhalation of dry powder inhalation by COPD patients to steady state, urinary excretion is 7% (1.3 µg) of the unchanged dose over 24 hours, the remainder being mainly non-absorbed drug in gut that is eliminated via the feces. The renal clearance of Tiotropium exceeds the creatinine clearance, indicating secretion into the urine. After chronic once daily inhalation by COPD patients, pharmacokinetic steady state was reached after 2-3 weeks with no accumulation thereafter.
Linearity/nonlinearity: Tiotropium demonstrates linear pharmacokinetics in the therapeutic range independent of the formulation.
Special Populations: Elderly Patients: As expected for all predominantly renally excreted drugs, 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). This did not result in a corresponding increase in AUC_0-6,ss and C_max,ss values.
Renally Impaired Patients: Following once daily inhaled administrations of Tiotropium to steady-state in COPD patients, with mild renal impairment (CL_CR 50-80 mL/min) resulted in slightly higher AUC_0-6,ss (between 1.8-30% higher) and similar C_max,ss values compared to patients with normal renal function (CL_CR >80 mL/min).
In COPD patients with moderate to severe renal impairment (CL_CR <50 mL/min) the intravenous administration of Tiotropium resulted in doubling of the plasma concentrations (82% increase in AUC_0-4h) and 52% higher C_max compared to COPD patients with normal renal function, which was confirmed by plasma concentrations after dry powder inhalation.
Hepatically Impaired Patients: Liver insufficiency is not expected to have any relevant influence on Tiotropium pharmacokinetics. Tiotropium is predominantly cleared by renal elimination (74% in young healthy volunteers) and by simple non-enzymatic ester cleavage to pharmacologic inactive products.
Toxicology: The acute inhalation and oral toxicity in mice, rats, and dogs was low, therefore, toxic effects from acute human drug overdosage are unlikely. The single dose safety pharmacology studies showed the expected effects of an anticholinergic drug including mydriasis, increased heart rate and prolonged gastrointestinal transit time.
The side effects of the repeated dose studies in rats, mice and dogs were related to anticholinergic properties of Tiotropium including mydriasis, increased heart rate, constipation, decreased body weight gain, reduce salivary and lacrimal gland secretion. Other relevant changes noted were: mild irritancy of the upper respiratory tract in rats evidenced by rhinitis and epithelial changes of the nasal cavity and larynx, and prostatitis along with proteinaceous deposits and lithiasis in the bladder of the male rats, increased lung weights in rats and decreased heart weights in dogs.
In the reproduction studies in rabbits and rats harmful effects with respect to pregnancy, embryo/fetal development, parturition or postnatal development could only be demonstrated at maternally toxic dose levels. In a general reproduction and fertility study in rats, there was no indication of any adverse effect on fertility or mating performance of either treated parents of their offspring at any dosage.
In series of in vivo and in vitro mutagenicity assays, Tiotropium bromide monohydrate did not cause gene mutations in prokaryotes and in eukaryotes, chromosomal damage in vitro and in vivo conditions or primary DNA damage.