Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, anticholinergics ATC code: R03B B04

Mechanism of action
Tiotropium bromide is a long-acting, specific, muscarinic receptor antagonist, in clinical medicine often called an anticholinergic. By binding to the muscarinic receptors in the bronchial smooth musculature, tiotropium bromide inhibits the cholinergic (bronchoconstrictive) effects of acetylcholine, released from parasympathetic nerve endings. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5 In the airways, tiotropium bromide competitively and reversibly antagonises the M3 receptors, resulting in relaxation. The effect was dose dependent and lasted longer than 24h. The long duration is probably due to the very slow dissociation from the M 3 receptor, exhibiting a significantly longer dissociation half-life than ipratropium. As an N-quaternary anticholinergic, tiotropium bromide is topically (broncho-) selective when administered by inhalation, demonstrating an acceptable therapeutic range before systemic anticholinergic effects may occur.

Pharmacodynamic effect
The bronchodilation is primarily a local effect (on the airways), not a systemic one.
Dissociation from M2-receptors is faster than from M3, which in functional in vitro studies, elicited (kinetically controlled) receptor subtype selectivity of M 3 over M2. The high potency and slow receptor dissociation found its clinical correlate in significant and long-acting bronchodilation in patients with COPD.

Cardiac electrophysiology
Electrophysiology: In a dedicated QT study involving 53 healthy volunteers, SPIRIVA 18 mcg and 54 mcg (i.e. three times the therapeutic dose) over 12 days did not significantly prolong QT intervals of the ECG.

Clinical efficacy and safety
The clinical development programme included four one-year and two six-month randomised, double- blind studies in 2663 patients (1308 receiving tiotropium bromide). The one-year programme consisted of two placebo-controlled trials and two trials with an active control (ipratropium). The two six-month trials were both, salmeterol and placebo controlled. These studies included lung function and health outcome measures of dyspnoea, exacerbations and 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 which 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 PEFR (peak expiratory flow rate) as measured by patient’s daily recordings. The bronchodilator effects of tiotropium bromide were maintained throughout the one-year period of administration with no evidence of tolerance.

A randomised, placebo-controlled clinical study in 105 COPD patients demonstrated that bronchodilation was maintained throughout the 24 hour dosing interval in comparison to placebo regardless of whether the drug was administered in the morning or in the evening.

Long term clinical trials (6 months and to 1year)

Dyspnoea, Exercise tolerance
Tiotropium bromide significantly improved dyspnoea (as evaluated using the Transition Dyspnoea Index.). This improvement was maintained throughout the treatment period.

The impact of improvements in dyspnoeaon exercise tolerance was investigated in two randomised, double-blind, placebo-controlled trials in 433 patients with moderate to severe COPD. In these trials, six weeks of treatment with SPIRIVA significantly improved symptom-limited exercise endurance time during cycle ergometry at 75% of maximal work capacity by 19.7% (Trial A) and 28.3% (Trial B) compared with placebo.


Health-related Quality of Life
In a 9-month, randomized, double-blind, placebo-controlled clinical trial of 492 patients, SPIRIVA improved health-related quality of life as determined by the St. George’s Respiratory Questionnaire (SGRQ) total score. The proportion of patients treated with SPIRIVA which achieved a meaningful improvement in the SGRQ total score (i.e. > 4 units) was 10.9% higher compared with placebo (59.1% in the SPIRIVA groups vs. 48.2% in the placebo group (p=0.029). The mean difference between the groups was 4.19 units (p=0.001; confidence interval: 1.69 – 6.68). The improvements of the subdomains of the SGRQ-score were 8.19 units for “symptoms”, 3.91 units for “activity” and 3.61 units for “impact on daily life”. The improvements of all of these separate subdomains were statistically significant.


COPD Exacerbations
In a randomized, double-blind, placebo controlled trial of 1,829 patients with moderate to very severe COPD, tiotropium bromide statistically significantly reduced the proportion of patients who experienced exacerbations of COPD (32.2% to 27.8%) and statistically significantly reduced the number of exacerbations by 19% (1.05 to 0.85 events per patient year of exposure). In addition, 7.0% of patients in the tiotropium bromide group and 9.5% of patients in the placebo group were hospitalized due to a COPD exacerbation (p=0.056). The number of hospitalizations due to COPD was reduced by 30% (0.25 to 0.18 events per patient year of exposure).

A one-year randomised, double-blind, double-dummy, parallel-group trial compared the effect of treatment with 18 microgram of SPIRIVA once daily with that of 50 microgram of salmeterol HFA pMDI twice daily on the incidence of moderate and severe exacerbations in 7,376 patients with COPD and a history of exacerbations in the preceding year.

Table 1: Summary of exacerbation endpoints

Endpoint                          SPIRIVA              Salmeterol            Ratio                   p-value 18 microgram         50 microgram          (95% CI)
(HandiHaler)         (HFA pMDI)
N = 3,707            N = 3,669
Time [days] to first                     187                   145                   0.83               <0.001 exacerbation†                                                                   (0.77 - 0.90) Time to first severe                                                                 0.72               <0.001 -                    -
(hospitalised) exacerbation§                                                    (0.61 - 0.85) Patients with ≥1                    1,277 (34.4)          1,414 (38.5)              0.90                <0.001 exacerbation, n (%)*                                                            (0.85 - 0.95) Patients with ≥1 severe               262 (7.1)            336 (9.2)                 0.77               <0.001 (hospitalised) exacerbation,                                                    (0.66 - 0.89) n (%)*

†      Time [days] refers to 1st quartile of patients. Time to event analysis was done using Cox's proportional hazards regression model with (pooled) centre and treatment as covariate; ratio refers to hazard ratio.
§      Time to event analysis was done using Cox's proportional hazards regression model with (pooled) centre and treatment as covariate; ratio refers to hazard ratio. Time [days] for the 1st quartile of patients cannot be calculated, because proportion of patients with severe exacerbation is too low.
*      Number of patients with event were analysed using Cochran-Mantel-Haenszel test stratified by pooled centre; ratio refers to risk ratio.

Compared with salmeterol, SPIRIVA 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). SPIRIVA also increased the time to the first severe (hospitalised) exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001).

Long-term clinical trials (more than 1 year, up to 4 years)

In a 4-year, randomised, double-blind, placebo-controlled clinical trial of 5,993 randomised patients (3.006 receiving placebo and 2,987 receiving Spiriva), the improvement in FEV1 resulting from Spiriva, compared with placebo, remained constant throughout 4 years. A higher proportion of patients completed ≥ 45 months of treatment in the Spiriva group compared with the placebo group (63.8% vs. 55.4%, p<0.001). The annualized rate of decline of FEV1 compared to placebo was similar between Spiriva and placebo. 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 risk of respiratory failure (as recorded through adverse event reporting) by 19% (2.09 vs. 1.68 cases per 100 patient years, relative risk (tiotropium/placebo) = 0.81, 95% CI = 0.65, 0.999).
Tiotropium active-controlled study

A long-term, large scale randomised, double-blind, active-controlled study with an observation period up to 3 years has been performed to compare the efficacy and safety of Spiriva HandiHaler and Spiriva Respimat (5,694 patients receiving Spiriva HandiHaler; 5,711 patients receiving Spiriva Respimat). 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 numerically similar during the study with Spiriva HandiHaler and Spiriva Respimat (hazard ratio (Spiriva HandiHaler/Spiriva Respimat) 1.02 with a 95% CI of 0.97 to 1.08). The median number of days to the first COPD exacerbation was 719 days for Spiriva HandiHaler and 756 days for Spiriva Respimat.

The bronchodilator effect of Spiriva HandiHaler was sustained over 120 weeks, and was similar to Spiriva Respimat. The mean difference in trough FEV1 for Spiriva HandiHaler versus Spiriva Respimat was 0.010 L (95% CI -0.018 to 0.038 L).

In the post-marketing TioSpir study comparing Spiriva Respimat and Spiriva HandiHaler, all-cause mortality including vital status follow up was similar during the study with Spiriva HandiHaler and Spiriva Respimat (hazard ratio (Spiriva HandiHaler/Spiriva Respimat) 1.04 with a 95% CI of 0.91 to 1.19).

Paediatric population:
The European Medicines Agency has waived the obligation to submit results of studies with Spiriva in all subsets of the paediatric population in COPD and cystic fibrosis (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
a) General Introduction

Tiotropium bromide is a non-chiral quaternary ammonium compound and is sparingly soluble in water. Tiotropium bromide is administered by dry powder inhalation. Generally with the inhaled route of administration, the majority of the delivered dose is deposited in the gastro-intestinal tract, and to a lesser extent in the intended organ of the lung. Many of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy.

b) General Characteristics of the Active Substance after Administration of the Medicinal Product 
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%. Maximum tiotropium plasma concentrations were observed 5-7 minutes after inhalation

: At steady state, peak tiotropium plasma levels 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.
Systemic exposure following the inhalation of tiotropium via the HandiHaler device was similar to tiotropium inhaled via the Respimat inhaler.

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 bromide 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 74% of unchanged substance after an intravenous dose to young healthy volunteers. The ester tiotropium bromide is nonenzymatically cleaved to the alcohol (N-methylscopine) and acid compound (dithienylglycolic acid) that are inactive on muscarinic receptors. In-vitro experiments with human liver microsomes and human hepatocytes suggest that some further drug (< 20% of dose after intravenous administration) is metabolised by cytochrome P450 (CYP) dependent oxidation and subsequent glutathion conjugation to a variety of Phase II-metabolites.
In vitro studies in liver microsomes reveal that the enzymatic pathway can be inhibited by the CYP 2D6 (and 3A4) inhibitors, quinidine, ketoconazole and gestodene. Thus CYP 2D6 and 3A4 are
involved in 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 CYP 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.

Elimination: The half-life of tiotropium ranges between 27-45 h in COPD patients. Total clearance was 880 ml/min after an intravenous dose in young healthy volunteers. Intravenously administered tiotropium is mainly excreted unchanged in urine (74%). After dry powder inhalation by COPD patients to steady-state, urinary excretion is 7% (1.3 μg) of the unchanged drug over 24 hours, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces. 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 by day 7 with no accumulation thereafter.

Linearity / Nonlinearity: Tiotropium demonstrates linear pharmacokinetics in the therapeutic range independent of the formulation.

c) Characteristics in Patients

Geriatric Patients: As expected for all predominantly renally excreted drugs, advancing age was associated with a decrease of tiotropium renal clearance (365 mL/min in COPD patients < 65 years to 271 mL/min in COPD patients > 65 years). This did not result in a corresponding increase in AUC0-
6,ss or Cmax,ss values.


Renally Impaired Patients: Following once daily inhaled administrations of tiotropium to steady-state in COPD patients, mild renal impairment (CLCR 50-80 ml/min) resulted in slightly higher AUC0-6,ss (between 1.8-30% higher) and similar Cmax, ss values compared to patients with normal renal function(CLCR >80 ml/min).

In COPD patients with moderate to severe renal impairment (CLCR < 50 ml/min), the intravenous administration of tiotropium resulted in doubling of the total exposure (82% higher AUC0-4h and 52% higher Cmax) 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 simple non-enzymatic ester cleavage to pharmacologically inactive products.

Japanese COPD Patients: In cross trial comparison, mean peak tiotropium plasma concentrations 10 minutes post-dosing at steady-state were 20% to 70% higher in Japanese compared to Caucasian COPD patients following inhalation of tiotropium but there was no signal for higher mortality or cardiac risk in Japanese patients compared to Caucasian patients. Insufficient pharmacokinetic data is available for other ethnicities or races.

Paediatric Patients: See section 4.2

d) Pharmacokinetic / Pharmacodynamic Relationship(s)
There is no direct relationship between pharmacokinetics and pharmacodynamics.