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 antagonist at muscarinic receptors. It has similar affinity to the subtypes, M1 to M5. In the airways, tiotropium bromide competitively and reversibly binds to the M3 receptors in the bronchial smooth musculature, antagonising the cholinergic (bronchoconstrictive) effects of acetylcholine, resulting in bronchial smooth muscle relaxation. The effect was dose dependent and lasted longer than 24h. 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 effects
The dissociation of tiotropium from especially M3-receptors is very slow, exhibiting a significantly longer dissociation half-life than ipratropium. Dissociation from M2-receptors is faster than from M3, which in functional in vitro studies, elicited (kinetically controlled) receptor subtype selectivity of M3 over M2. The high potency, very slow receptor dissociation and topical inhaled selectivity found its clinical correlate in significant and long-acting bronchodilation in patients with COPD and asthma.

Clinical efficacy and safety in COPD
The clinical Phase III development programme included two 1-year, two 12-weeks and two 4-weeks randomised, double-blind studies in 2901 COPD patients (1038 receiving the 5 µg tiotropium dose).
The 1-year programme consisted of two placebo-controlled trials. The two 12-week trials were both active (ipratropium) - and placebo-controlled. All six studies included lung function measurements. In addition, the two 1-year studies included health outcome measures of dyspnoea, health-related quality of life and effect on exacerbations.

Placebo-controlled studies

Lung function
Tiotropium inhalation solution, administered once daily, provided significant improvement in lung function (forced expiratory volume in one second and forced vital capacity) within 30 minutes following the first dose, compared to placebo (FEV1 mean improvement at 30 minutes: 0.113 litres; 95% confidence interval (CI): 0.102 to 0.125 litres, p< 0.0001). Improvement of lung function was maintained for 24 hours at steady state compared to placebo (FEV1 mean improvement: 0.122 litres; 95% CI: 0.106 to 0.138 litres, p< 0.0001).
Pharmacodynamic steady state was reached within one week.

Spiriva Respimat significantly improved morning and evening PEFR (peak expiratory flow rate) as measured by patient's daily recordings compared to placebo (PEFR mean improvement: mean improvement in the morning 22 L/min; 95% CI: 18 to 55 L/min, p< 0.0001; evening 26 L/min; 95% CI: 23 to 30 L/min, p<0.0001). The use of Spiriva Respimat resulted in a reduction of rescue bronchodilator use compared to placebo (mean reduction in rescue use 0.66 occasions per day, 95% CI: 0.51 to 0.81 occasions per day, p<0.0001).

The bronchodilator effects of Spiriva Respimat were maintained throughout the 1-year period of administration with no evidence of tolerance.



Spiriva Respimat                                           Prescribing information Solution for inhalation                                    July 2019
Dyspnoea, Health-related Quality of Life, COPD Exacerbations in long term 1 year studies 
Dyspnoea
Spiriva Respimat significantly improved dyspnoea (as evaluated using the Transition Dyspnoea Index) compared to placebo (mean improvement 1.05 units; 95% CI: 0.73 to 1.38 units, p<0.0001). An improvement was maintained throughout the treatment period.

Health-related Quality of Life
The improvement in mean total score of patient’s evaluation of their Quality of Life (as measured using the St. George’s Respiratory Questionnaire) between Spiriva Respimat versus placebo at the end of the two 1-year studies was 3.5 units (95% CI: 2.1 to 4.9, p<0.0001). A 4-unit decrease is considered clinically relevant.

COPD Exacerbations
In three one-year, randomised, double-blind, placebo-controlled clinical trials Spiriva Respimat treatment resulted in a significantly reduced risk of a COPD exacerbation in comparison to placebo.
Exacerbations of COPD were defined as “a complex of at least two respiratory events/symptoms with a duration of three days or more requiring a change in treatment (prescription of antibiotics and/or systemic corticosteroids and/or a significant change of the prescribed respiratory medication)”.
Spiriva Respimat treatment resulted in a reduced risk of a hospitalisation due to a COPD exacerbation (significant in the appropriately powered large exacerbation trial).
The pooled analysis of two Phase III trials and separate analysis of an additional exacerbation trial is displayed in Table 1. All respiratory medications except anticholinergics and long-acting beta-agonists were allowed as concomitant treatment, i.e. rapidly acting beta-agonists, inhaled corticosteroids and xanthines. Long-acting beta-agonists were allowed in addition in the exacerbation trial.

Table 1: Statistical Analysis of Exacerbations of COPD and Hospitalized COPD Exacerbations in Patients with Moderate to Very Severe COPD
Study                  Endpoint                                Spiriva    Placebo         % Risk         p-value (NSpiriva, Nplacebo)                                          Respimat                  Reduction (95% CI)a a             a
1-year Ph III         Days to first COPD exacerbation          160            86            29        <0.0001b studies,                                                                              (16 to 40)b d                                                  c               c pooled analysis       Mean exacerbation incidence rate        0.78          1.00            22          0.002c c per patient year                                                  (8 to 33) (670, 653)            Time to first hospitalised COPD                                       25           0.20b b exacerbation                                                    (-16 to 51) Mean hospitalised exacerbation          0.09 c        0.11 c          20          0.096 c incidence rate per patient year                                  (-4 to 38) c a              a
1-year Ph IIIb        Days to first COPD exacerbation          169           119            31         <0.0001b b exacerbation                                                                          (23 to 37) study                 Mean exacerbation                       0.69c         0.87c           21         <0.0001c c incidence rate per patient year                                  (13 to 28) (1939, 1953)          Time to first hospitalised COPD                                       27          0.003b b exacerbation                                                    (10 to 41) c               c
Mean hospitalised exacerbation          0.12          0.15            19          0.004c c incidence rate per patient year                                   (7 to 30) a
Time to first event: days on treatment by when 25% of patients had at least one exacerbation of COPD / hospitalized COPD exacerbation. In study A 25% of placebo patients had an exacerbation by day 112, whereas for Spiriva Respimat 25% had an exacerbation by day 173 ( p=0.09);in study B 25% of placebo patients had an exacerbation by day 74, whereas for Spiriva Respimat 25% had an exacerbation by day 149 (p<0.0001).
b
Hazard ratios were estimated from a Cox proportional hazard model. The percentage risk reduction is 100(1 - hazard ratio).
c
Poisson regression. Risk reduction is 100(1 - rate ratio).

Spiriva Respimat                                          Prescribing information Solution for inhalation                                   July 2019 d
Pooling was specified when the studies were designed. The exacerbation endpoints were significantly improved in individual analyses of the two one year studies.

Long-term 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 Respimat and Spiriva HandiHaler (5,711 patients receiving Spiriva Respimat; 5,694 patients receiving Spiriva HandiHaler). 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 Respimat and Spiriva HandiHaler (hazard ratio (Spiriva Respimat/Spiriva 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 Spiriva Respimat and 719 days for Spiriva HandiHaler.

The bronchodilator effect of Spiriva Respimat was sustained over 120 weeks, and was similar to Spiriva HandiHaler. The mean difference in trough FEV1 for Spiriva Respimat versus Spiriva HandiHaler was -0.010 L (95% CI -0.038 to 0.018 L).
In the post-marketing TIOSPIR study comparing Spiriva Respimat and Spiriva HandiHaler, all-cause mortality (including vital status follow up) was similar with hazard ratio (Spiriva Respimat/Spiriva HandiHaler) = 0.96 , 95% CI 0.84 -1.09). Respective treatment exposure was 13,135 and 13,050 patient-years.
In the placebo-controlled studies with vital status follow-up to the end of the intended treatment period, Spiriva Respimat showed a numerical increase in all-cause mortality compared to placebo (rate ratio (95% confidence interval) of 1.33 (0.93, 1.92) with treatment exposure to Spiriva Respimat of 2,574 patient years; the excess in mortality was observed in patients with known rhythm disorders.
Spiriva HandiHaler showed a 13 % reduction in the risk of death ((hazard ratio including vital status follow-up (tiotropium/placebo) = 0.87; 95% CI, 0.76 to 0.99)). Treatment exposure to Spiriva HandiHaler was 10,927 patient-years. No excess mortality risk was observed in the subgroup of patients with known rhythm disorders in the placebo controlled Spiriva HandiHaler study as well as in the TIOSPIR Spiriva Respimat to HandiHaler comparison.

Clinical efficacy and safety in asthma

The clinical Phase III programme for persistent asthma in adults included two 1-year randomised, double-blind, placebo-controlled studies in a total of 907 asthma patients (453 receiving Spiriva Respimat) on a combination of ICS (≥800 µg budesonide/day or equivalent) with a LABA. The studies included lung function measurements and severe exacerbations as primary endpoints.

PrimoTinA-asthma studies
In the two 1-year studies in patients who were symptomatic on maintenance treatment of at least ICS (≥800 µg budesonide/day or equivalent) plus LABA, Spiriva Respimat showed clinically relevant improvements in lung function over placebo when used as add-on to background treatment.

At week 24, mean improvements in peak and trough FEV1 were 0.110 litres (95% CI: 0.063 to 0.158 litres, p<0.0001) and 0.093 litres (95% CI: 0.050 to 0.137 litres, p<0.0001), respectively. The improvement of lung function compared to placebo was maintained for 24 hours.

In the PrimoTinA-asthma studies, treatment of symptomatic patients (N=453) with ICS plus LABA plus tiotropium reduced the risk of severe asthma exacerbations by 21% as compared to treatment of symptomatic patients (N=454) with ICS plus LABA plus placebo. The risk reduction in the mean number of severe asthma exacerbations/patient year was 20%.


Spiriva Respimat                                                 Prescribing information Solution for inhalation                                          July 2019 This was supported by a reduction of 31% in risk for asthma worsening and 24% risk reduction in the mean number of asthma worsenings/patient year (see Table 2).

Table 2: Exacerbations in Patients Symptomatic on ICS (≥800 µg budesonide/day or equivalent) plus LABA (PrimoTinA-asthma studies)

Study              Endpoint                     Spiriva Respimat,      Placebo,                % Risk          p-value added-on to at         added-on to at          Reduction least ICSa/LABA        least ICSa/LABA         (95% CI)
(N=453)                (N=454)

 two 1-year         Days to 1st severe           282c                   226c                    21b             0.0343 Phase III          asthma exacerbation                                                         (0, 38) studies,
pooled analysis    Mean number of severe        0.530                  0.663                   20d             0.0458 asthma exacerbations/                                                       (0, 36) patient year

Days to 1st worsening        315c                   181c                    31b             <0.0001 of asthma                                                                   (18, 42) 
Mean number of               2.145                  2.835                   24d             0.0031 asthma worsenings/                                                          (9, 37) patient year a  ≥800 µg budesonide/day or equivalent b  Hazard ratio, confidence interval and p-value obtained from a Cox proportional hazards model with only treatment as effect. The percentage risk reduction is 100(1 - hazard ratio).
c Time to first event: days on treatment by when 25%/50% of patients had at least one severe asthma exacerbation/worsening  of asthma d The rate ratio was obtained from a Poisson regression with log exposure (in years) as offset. The percentage risk reduction  is 100 (1-rate ratio).

Paediatric population


Asthma
All studies in the clinical Phase III program for persistent asthma in paediatric patients (1 - 17 years) were randomised, double-blind and placebo-controlled. All patients were on background treatments that include an ICS.

Severe Asthma
Adolescents (12 - 17 years)
In the 12-week PensieTinA-asthma study a total of 392 patients (130 receiving Spiriva Respimat) who were symptomatic on a high dose of ICS with one controller or a medium dose of ICS with 2 controllers were included.

For patients aged 12 - 17 years, a high dose ICS was defined as a dose of > 800 - 1600 µg budesonide/day or equivalent; a medium dose ICS as 400 - 800 µg budesonide/day or equivalent. In addition, patients aged 12 - 14 years could receive an ICS dose > 400 µg budesonide/day or equivalent and at least one controller or ≥ 200 µg budesonide/day or equivalent and at least two controllers.

In this study, Spiriva Respimat showed improvements in lung function over placebo when used as add-on to background treatment, however, the differences in peak and trough FEV1 were not statistically significant.

Spiriva Respimat                                      Prescribing information Solution for inhalation                               July 2019

• At week 12, mean improvements in peak and trough FEV1 were 0.090 litres (95% CI: -0.019 to 0.198 litres, p=0.1039) and 0.054 litres (95% CI: -0.061 to 0.168 litres, p=0.3605), respectively.
• At week 12, Spiriva Respimat significantly improved morning and evening PEF (morning 17.4 L/min; 95% CI: 5.1 to 29.6 L/min; evening 17.6 L/min; 95% CI: 5.9 to 29.6 L/min).

Children (6 - 11 years)
In the 12-week VivaTinA-asthma study a total 400 patients (130 receiving Spiriva Respimat) who were symptomatic on a high dose ICS with one controller or a medium dose ICS with 2 controllers were included. A high dose ICS was defined by a dose of > 400 µg budesonide/day or equivalent, a medium dose as 200 - 400 µg budesonide/day or equivalent.
In this study, Spiriva Respimat showed significant improvements in lung function over placebo when used as add-on to background treatment.

• At week 12, mean improvements in peak and trough FEV1 were 0.139 litres (95% CI: 0.075 to 0.203 litres, p<0.0001) and 0.087 litres (95% CI: 0.019 to 0.154 litres, p=0.0117), respectively.


Moderate Asthma
Adolescents (12 - 17 years)
In the 1-year RubaTinA-asthma study in a total of 397 patients (134 receiving Spiriva Respimat) who were symptomatic on a medium dose ICS (200 - 800 µg budesonide/day or equivalent for patients aged 12 - 14 years or 400 - 800 µg budesonide/day or equivalent for patients aged 15 - 17 years), Spiriva Respimat showed significant improvements in lung function over placebo when used as add-on to background treatment.

Children (6 - 11 years)
In the 1-year CanoTinA-asthma study in a total of 401 patients (135 receiving Spiriva Respimat) who were symptomatic on a medium dose ICS (200 - 400 µg budesonide/day or equivalent), Spiriva Respimat showed significant improvements in lung function over placebo when used as add-on to background treatment.

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 available as inhalation solution administered by the Respimat inhaler.
Approximately 40% of the inhaled dose is deposited in the lungs, the target organ, the remaining amount being deposited in the gastrointestinal tract. Some 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 inhalation by young healthy volunteers, urinary excretion data suggests that approximately 33% of the inhaled dose reaches the systemic circulation. Oral solutions of tiotropium bromide have an absolute bioavailability of 2-3%. Food is not expected to influence the absorption of this quaternary ammonium compound.
Maximum tiotropium plasma concentrations were observed 5-7 minutes after inhalation.


Spiriva Respimat                                       Prescribing information Solution for inhalation                                July 2019
At steady state, peak tiotropium plasma levels in COPD patients of 10.5 pg/ml were achieved and decreased rapidly in a multi-compartmental manner. Steady state trough plasma concentrations were 1.60 pg/ml.
A steady state tiotropium peak plasma concentration of 5.15 pg/ml was attained 5 minutes after the administration of the same dose to patients with asthma.
Systemic exposure to tiotropium following the inhalation of tiotropium via the Respimat inhaler was similar to tiotropium inhaled via the HandiHaler device.

Distribution: The drug 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 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 effective half-life of tiotropium ranges between 27 - 45 h following inhalation by healthy volunteers and COPD patients. The effective half-life was 34 hours in patients with asthma.
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 inhalation of the solution by COPD patients to steady-state, urinary excretion is 18.6 % (0.93 µg) of the dose, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces.
After inhalation of the solution by healthy volunteers urinary excretion is 20.1-29.4 % of the dose, the remainder being mainly non-absorbed drug in gut that is eliminated via the faeces.
In patients with asthma, 11.9% (0.595 µg) of the dose is excreted unchanged in the urine over 24 hours post dose at steady state. 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 (347 ml/min in COPD patients < 65 years to 275 ml/min in COPD patients ≥65 years). This did not result in a corresponding increase in AUC0-6,ss or Cmax,ss values. Exposure to tiotropium was not found to differ with age in patients with asthma.

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).

Spiriva Respimat                                         Prescribing information Solution for inhalation                                  July 2019
In COPD patients with moderate to severe renal impairment (CLCR < 50 ml/min), the intravenous administration of a single dose 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.
In asthma patients with mild renal impairment (CLCR 50-80 ml/min) inhaled tiotropium did not result in relevant increases in exposure compared to patients with normal renal function.

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:
Asthma
The peak and total (AUC and urinary excretion) exposure to tiotropium is comparable between patients with asthma who were 6 - 11 years old, 12 - 17 years old and ≥18 years old. Based on urinary excretion, the total exposure to tiotropium in patients 1 to 5 years of age was 52 to 60% lower than in other older age groups. The total exposure data when adjusted for body surface area were found to be comparable in all age groups. Spiriva Respimat was administered with a valved holding chamber with face mask in patients 1 to 5 years of age.

COPD
There were no paediatric patients in the COPD programme (see 4.2).

Cystic Fibrosis
Following inhalation of 5 µg tiotropium, the tiotropium plasma level in CF patients ≥5 years was 10.1 pg/ml 5 minutes post-dosing at steady-state and decreased rapidly thereafter. The fraction of the dose available in CF patients <5 years old who used the spacer and mask was approximately 3- to 4- fold lower than that observed in CF patients 5 years and older. Tiotropium exposure was related to body-weight in CF patients <5 years.
 d) Pharmacokinetic / Pharmacodynamic Relationship(s)

There is no direct relationship between pharmacokinetics and pharmacodynamics.