Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for obstructive airway diseases, anticholinergics, ATC code: R03BB07 
Mechanism of action

Umeclidinium is a long acting muscarinic receptor antagonist (also referred to as an anticholinergic). It is a quinuclidine derivative that is a muscarinic receptor antagonist with activity across multiple muscarinic cholinergic receptor subtypes. Umeclidinium exerts its bronchodilatory activity by competitively inhibiting the binding of acetylcholine with muscarinic cholinergic receptors on airway smooth muscle. It demonstrates slow reversibility at the human M3 muscarinic receptor subtype in vitro and a long duration of action in vivo when administered directly to the lungs in pre-clinical models.

Pharmacodynamic effects

In a Phase III, 6-month study (DB2113373) umeclidinium provided a clinically meaningful improvement over placebo in lung function (as measured by forced expiratory volume in 1 second [FEV1]) over 24 hours following once daily administration, which was evident at 30 minutes following administration of the first dose (improvement over placebo by 102 mL, p<0.001*). The mean peak improvements in FEV1 within the first 6 hours following dosing relative to placebo were 130 mL (p<0.001*) at week 24. There was no evidence for tachyphylaxis in the effect of umeclidinium over time.

Cardiac electrophysiology
The effect of umeclidinium 500 micrograms (pre-dispensed) on the QT interval was evaluated in a placebo- and moxifloxacin-controlled QT trial of 103 healthy volunteers. Following repeat doses of umeclidinium 500 micrograms once daily for 10 days, no clinically relevant effect on prolongation of QT interval (corrected using the Fridericia method) or effects on heart rate were observed.

Clinical efficacy and safety

The clinical efficacy of umeclidinium administered once daily was evaluated in 904 adult patients who received umeclidinium or placebo from two pivotal Phase III clinical studies with a clinical diagnosis of COPD; a 12-week study (AC4115408) and a 24-week study (DB2113373).

Pivotal efficacy studies:

Effects on lung function
In both of the pivotal 12-week and 24-week studies, umeclidinium demonstrated statistically significant and clinically meaningful improvements in lung function (as defined by change from baseline trough FEV1 at week 12 and week 24 respectively, which was the primary efficacy endpoint in each study) compared with placebo (see Table 1). The bronchodilatory effects with umeclidinium compared with placebo were evident after the first day of treatment in both studies and were maintained over the 12-week and 24-week treatment periods.

There was no attenuation of the bronchodilator effect over time.



*
A step-down statistical testing procedure was used in this study and this comparison was below a comparison that did not achieve statistical significance. Therefore, statistical significance on this comparison cannot be inferred.


Table 1: Trough FEV1 (mL) at week 12 and week 24 (primary endpoint)
Treatment with                 12-week study                            24-week study umeclidinium 55 mcg           Treatment difference1                    Treatment difference1 95% Confidence interval                  95% Confidence interval p-value                                  p-value
Versus                                  127                                      115 Placebo                              (52, 202)                                (76, 155) <0.001                                   <0.001 mcg = micrograms
1.
least squares mean (95% confidence interval)

Umeclidinium demonstrated a statistically significant greater improvement from baseline in weighted mean FEV1 over 0-6 hours post-dose at week 12 compared with placebo (166 mL, p<0.001) in the 12-week pivotal study. Umeclidinium demonstrated a greater improvement from baseline in weighted mean FEV1 over 0-6 hours post-dose at week 24 compared with placebo (150 mL, p<0.001*) in the 24-week pivotal study.

Symptomatic outcomes

Breathlessness:
In the 12-week study, a statistically significant improvement compared with placebo in the TDI focal score at week 12 was not demonstrated for umeclidinium (1.0 units, p=0.05). A statistically significant improvement compared with placebo in the TDI focal score at week 24 was demonstrated for umeclidinium (1.0 units, p<0.001) in the 24-week study.

The proportion of patients who responded with at least the minimum clinically important difference (MCID) of 1 unit TDI focal score at week 12 was greater for umeclidinium (38%) compared with placebo (15%) in the 12-week study. Similarly, a greater proportion of patients achieved 1 unit TDI focal score for umeclidinium (53%) compared with placebo (41%) at week 24 in the 24-week study.

Health-related quality of life:
Umeclidinium also demonstrated a statistically significant improvement in health-related quality of life measured using the St. George’s Respiratory Questionnaire (SGRQ) as indicated by a reduction in SGRQ total score at week 12 compared with placebo (-7.90 units, p<0.001) in the 12-week study. A greater improvement compared with placebo in the change from baseline in SGRQ total score at week 24 was demonstrated for umeclidinium (-4.69 units, p<0.001) in the 24-week study.

The proportion of patients who responded with at least the MCID in SGRQ score (defined as a decrease of 4 units from baseline) at week 12 was greater for umeclidinium 55 micrograms (44%) compared with placebo (26%) in the 12-week study. Similarly, a greater proportion of patients achieved at least the MCID for umeclidinium at week 24 (44%) compared with placebo (34%) in the 24-week study.

COPD exacerbations
In the 24-week placebo-controlled study in patients with symptomatic COPD, umeclidinium reduced the risk of a moderate/severe COPD exacerbation by 40% compared with placebo (analysis of time to first exacerbation; Hazard Ratio 0.6; 95% CI: 0.4, 1.0, p=0.035*). The probability of having an exacerbation in patients receiving umeclidinium at week 24 was 8.9% compared with 13.7% for placebo. These studies were not specifically designed to evaluate the effect of treatments on COPD exacerbations and patients were withdrawn from the study if an exacerbation occurred.


*
A step-down statistical testing procedure was used in this study and this comparison was below a comparison that did not achieve statistical significance. Therefore, statistical significance on this comparison cannot be inferred.
.

Use of rescue medicinal product
In the 12-week study, umeclidinium statistically significantly reduced the use of rescue medication with salbutamol compared with placebo (on average a reduction of 0.7 puffs per day over weeks 1-12, p=0.025) and demonstrated a higher percentage of days when no rescue medication was needed (on average 46.3%) compared with placebo (on average 35.2%; no formal statistical analysis was performed on this endpoint). In the 24-week study treatment with umeclidinium, the mean (SD) change from baseline in the number of puffs of rescue salbutamol over the 24-week treatment period was -1.4 (0.20) for placebo and -1.7 (0.16) for umeclidinium (Difference = -0.3; 95% CI: -0.8, 0.2, p=0.276). Patients receiving umeclidinium had a higher percentage of days when no rescue medication was needed (on average 31.1%) compared with placebo (on average 21.7%). No formal statistical testing was performed on this endpoint.

Supporting efficacy studies
In a randomised, double-blind, 52-week study (CTT116855, IMPACT) of 10,355 adult patients with symptomatic COPD and a history of 1 or more moderate or severe exacerbations within the prior 12 months, treatment with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI 92/55/22 micrograms) once daily as a single inhaler was compared with fluticasone furoate/vilanterol (FF/VI 92/22 micrograms) once daily as a single inhaler. The primary endpoint was annual rate of on-treatment moderate and severe exacerbations in subjects treated with FF/UMC/VI compared with FF/VI. The mean annual rate of exacerbations was 0.91 and 1.07 for FF/UMEC/VI and FF/VI respectively (Rate Ratio: 0.85; 95% CI: 0.80, 0.90; p<0.001).
At week 52, a statistically significant improvement in the least-squares (LS) mean change from baseline in trough FEV1 was observed for FF/UMEC/VI compared with FF/VI (mean change: +94 mL vs. -3 mL; treatment difference: 97 mL; 95% CI: 85, 109; p<0.001).

In two 12-week, placebo controlled studies (200109 and 200110), the addition of umeclidinium to fluticasone furoate/vilanterol (FF/VI) (92/22 micrograms) once daily in adult patients with a clinical diagnosis of COPD, resulted in statistically significant and clinically meaningful improvements in the primary endpoint of trough FEV1 at Day 85 compared to placebo plus FF/VI (124 mL 95% CI: 93, 154; p<0.001 and 122 mL 95% CI: 91, 152; p<0.001).

Improvements in lung function were supported with reductions in use of salbutamol over weeks 1-12 (-0.4 puffs per day (95% CI: -0.7, -0.2; p<0.001) and -0.3 puffs per day (95% CI: -0.5, -0.1; p=0.003)) compared to placebo plus FF/VI but improvements in SGRQ at week 12 were not statistically significant (200109) or clinically relevant (200109 and 200110). The short duration of these two studies and limited number of exacerbation events, preclude any conclusion regarding additional effect of umeclidinium on COPD exacerbation rate.

No new adverse drug reactions were identified with the addition of umeclidinium to FF/VI in these studies.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption

Following inhaled administration of umeclidinium in healthy volunteers, Cmax occurred at 5 to 15 minutes.
The absolute bioavailability of inhaled umeclidinium was on average 13% of the dose, with negligible contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, steady state was achieved within 7 to 10 days with 1.5 to 1.8-fold accumulation.

Distribution

Following intravenous administration to healthy subjects, the mean volume of distribution was 86 litres.
In vitro plasma protein binding in human plasma was on average 89%.
Biotransformation


In vitro studies showed that umeclidinium is principally metabolised by cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (glucuronidation, etc), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low.

Elimination

Plasma clearance following intravenous administration was 151 litres/hour. Following intravenous administration, approximately 58% of the administered radiolabelled dose (or 73% of the recovered radioactivity) was excreted in faeces by 192 hours post-dose. Urinary elimination accounted for 22% of the administered radiolabelled dose by 168 hours (27% of recovered radioactivity). The excretion of the material in the faeces following intravenous dosing indicated secretion into the bile. Following oral administration to healthy male subjects, total radioactivity was excreted primarily in faeces (92% of the administered radiolabelled dose or 99% of the recovered radioactivity) by 168 hours post-dose. Less than 1% of the orally administered dose (1% of recovered radioactivity) was excreted in urine, suggesting negligible absorption following oral administration. Umeclidinium plasma elimination half-life following inhaled dosing for 10 days averaged 19 hours, with 3% to 4% active substance excreted unchanged in urine at steady-state.

Special populations

Elderly
A population pharmacokinetic analysis showed that pharmacokinetics of umeclidinium are similar between COPD patients 65 years or older and those younger than 65 years of age.

Renal impairment
Subjects with severe renal impairment (creatinine clearance <30 mL/min) showed no evidence of an increase in systemic exposure to umeclidinium (Cmax and AUC), and no evidence of altered protein binding between subjects with severe renal impairment and healthy volunteers.

Hepatic impairment
Subjects with moderate hepatic impairment (Child-Pugh Class B) showed no evidence of an increase in systemic exposure to umeclidinium (Cmax and AUC), and no evidence of altered protein binding between subjects with moderate hepatic impairment and healthy volunteers. Umeclidinium has not been evaluated in subjects with severe hepatic impairment.

Other special populations
A population pharmacokinetic analysis showed that no dose adjustment is required for umeclidinium based on the effect of age, race, gender, inhaled corticosteroid use or weight. A study in CYP2D6 poor metabolisers showed no evidence of a clinically significant effect of CYP2D6 genetic polymorphism on systemic exposure to umeclidinium.