Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for obstructive airways diseases, selective beta-2-
adrenoreceptor agonists, ATC code: R03AC18


Mechanism of action
The pharmacological effects of beta2-adrenoceptor agonists are at least in part attributable to
stimulation of intracellular adenyl cyclase, the enzyme that catalyses the conversion of
adenosine triphosphate (ATP) to cyclic-3’, 5’-adenosine monophosphate (cyclic
monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle.
In vitro studies have shown that indacaterol, a long-acting beta2-adrenergic agonist, has more
than 24-fold greater agonist activity at beta2-receptors compared to beta1-receptors and 20-
fold greater agonist activity compared to beta3-receptors.
When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a partial
agonist at the human beta2-adrenergic receptor with nanomolar potency. In isolated human
bronchus, indacaterol has a rapid onset of action and a long duration of action.
Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth
muscle and beta1-receptors are the predominant receptors in the human heart, there are also
beta2-adrenergic receptors in the human heart comprising 10-50% of the total adrenergic
receptors. The precise function of beta2-adrenergic receptors in the heart is not known, but

ONB API JUN21 V1.1                                                    Ref EMA SmPC 15Dec2020
their presence raises the possibility that even highly selective beta2-adrenergic agonists may
have cardiac effects.

Pharmacodynamic effects
Onbrez Breezhaler, administered once a day at doses of 150 and 300 microgram consistently
provided clinically significant improvements in lung function (as measured by the forced
expiratory volume in one second, FEV1) over 24 hours across a number of clinical
pharmacodynamic and efficacy studies. There was a rapid onset of action within 5 minutes
after inhalation, with an increase in FEV1 relative to baseline of 110-160 ml, comparable to
the effect of the fast-acting beta2-agonist salbutamol 200 microgram and statistically
significantly faster compared to salmeterol/fluticasone 50/500 microgram. Mean peak
improvements in FEV1 relative to baseline were 250-330 ml at steady state.
The bronchodilator effect did not depend on the time of dosing, morning or evening.
Onbrez Breezhaler was shown to reduce lung hyperinflation, resulting in increased inspiratory
capacity during exercise and at rest, compared to placebo.

Effects on cardiac electrophysiology
A double-blind, placebo- and active (moxifloxacin)-controlled study for 2 weeks in 404
healthy volunteers demonstrated maximum mean (90% confidence intervals) prolongations of
the QTcF interval (in milliseconds) of 2.66 (0.55, 4.77) 2.98 (1.02, 4.93) and 3.34 (0.86, 5.82)
following multiple doses of 150 microgram, 300 microgram and 600 microgram, respectively.
There was no evidence of a concentration-delta QTc relationship in the range of doses
evaluated.
As demonstrated in 605 patients with COPD in a 26-week, double-blind, placebo-controlled
Phase III study, there was no clinically relevant difference in the development of arrhythmic
events monitored over 24 hours, at baseline and up to 3 times during the 26-week treatment
period, between patients receiving recommended doses of Onbrez Breezhaler treatment and
those patients who received placebo or treatment with tiotropium.

Clinical efficacy and safety
The clinical development programme included one 12-week, two six-month (one of which
was extended to one year to evaluate safety and tolerability) and one one-year randomised
controlled studies in patients with a clinical diagnosis of COPD. These studies included
measures of lung function and of health outcomes such as dyspnoea, exacerbations and
health-related quality of life.

Lung function
Onbrez Breezhaler, administered once a day at doses of 150 microgram and 300 microgram,
showed clinically meaningful improvements in lung function. At the 12-week primary
endpoint (24-hour trough FEV1), the 150 microgram dose resulted in a 130-180 ml increase
compared to placebo (p<0.001) and a 60 ml increase compared to salmeterol 50 microgram
twice a day (p<0.001). The 300 microgram dose resulted in a 170-180 ml increase compared
to placebo (p<0.001) and a 100 ml increase compared to formoterol 12 microgram twice a day
(p<0.001). Both doses resulted in an increase of 40-50 ml over open-label tiotropium
18 microgram once a day (150 microgram, p=0.004; 300 microgram, p=0.01). The 24-hour
bronchodilator effect of Onbrez Breezhaler was maintained from the first dose throughout a
one-year treatment period with no evidence of loss in efficacy (tachyphylaxis).

ONB API JUN21 V1.1                                                    Ref EMA SmPC 15Dec2020
Symptomatic benefits
Both doses demonstrated statistically significant improvements in symptom relief over
placebo for dyspnoea and health status (as evaluated by Transitional Dyspnoea Index [TDI]
and St. George’s Respiratory Questionnaire [SGRQ], respectively). The magnitude of
response was generally greater than seen with active comparators (Table 2). In addition,
patients treated with Onbrez Breezhaler required significantly less rescue medication, had
more days when no rescue medication was needed compared to placebo and had a
significantly improved percentage of days with no daytime symptoms.
Pooled efficacy analysis over 6 months’ treatment demonstrated that the rate of COPD
exacerbations was statistically significantly lower than the placebo rate. Treatment
comparison compared to placebo showed a ratio of rates of 0.68 (95% CI [0.47, 0.98]; p-value
0.036) and 0.74 (95% CI [0.56, 0.96]; p-value 0.026) for 150 microgram and 300 microgram,
respectively.
Limited treatment experience is available in individuals of African descent.


Table 2        Symptom relief at 6 months treatment duration
Treatment          Indacater Indacater Tiotropiu Salmetero Formoter Placeb
Dose                    ol           ol           m            l             ol           o
(microgram)            150          300          18           50             12
                   once a day once a day once a day         twice a       twice a
                                                              day           day
Percentage of
                       57 a                                   54 a                      45 a
patients who
                       62 b         71 b         57 b                                   47 b
achieved                                c                                       c
                                    59                                      54          41 c
MCID TDI†
Percentage of
                       53 a                                   49 a                      38 a
patients who
                       58 b         53 b         47 b                                   46 b
achieved                                c                                       c
                                    55                                      51          40 c
MCID SGRQ†
Reduction in
puffs/day of           1.3 a                                 1.2 a                      0.3 a
                           b            b           b
rescue                 1.5          1.6         1.0                          n/e        0.4 b
medication use
vs. baseline
Percentage of
                       60 a                                   55 a                      42 a
days with no               b            b           b
                       57           58           46                          n/e        42 b
rescue
medication use
Study design with a: indacaterol 150 microgram, salmeterol and placebo; b: indacaterol 150
and 300 microgram, tiotropium and placebo; c: indacaterol 300 microgram, formoterol and
placebo
†
  MCID = minimal clinically important difference (≥1 point change in TDI, ≥4 point change
in SGRQ)
n/e= not evaluated at six months




ONB API JUN21 V1.1                                                  Ref EMA SmPC 15Dec2020

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Indacaterol is a chiral molecule with R-configuration.

Pharmacokinetic data were obtained from a number of clinical studies, from healthy
volunteers and COPD patients.
Absorption
The median time to reach peak serum concentrations of indacaterol was approximately 15 min
after single or repeated inhaled doses. Systemic exposure to indacaterol increased with
increasing dose (150 microgram to 600 microgram) in a dose proportional manner. Absolute
bioavailability of indacaterol after an inhaled dose was on average 43% to 45%. Systemic
exposure results from a composite of pulmonary and gastrointestinal absorption; about 75%
of systemic exposure was from pulmonary absorption and about 25% from gastrointestinal
absorption.
Indacaterol serum concentrations increased with repeated once-daily administration. Steady-
state was achieved within 12 to 14 days. The mean accumulation ratio of indacaterol, i.e.
AUC over the 24-h dosing interval on Day 14 compared to Day 1, was in the range of 2.9 to
3.5 for once-daily inhaled doses between 150 microgram and 600 microgram.
Distribution
After intravenous infusion the volume of distribution of indacaterol during the terminal
elimination phase was 2557 litres indicating an extensive distribution. The in vitro human
serum and plasma protein binding was 94.1-95.3% and 95.1-96.2%, respectively.
Biotransformation
After oral administration of radiolabelled indacaterol in a human ADME (absorption,
distribution, metabolism, excretion) study, unchanged indacaterol was the main component in
serum, accounting for about one third of total drug-related AUC over 24 hours. A
hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-
glucuronides of indacaterol and hydroxylated indacaterol were further prominent metabolites.
A diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-
dealkylated products were further metabolites identified.
In vitro investigations indicated that UGT1A1 is the only UGT isoform that metabolised
indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in
incubations with recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is concluded to be
the predominant isoenzyme responsible for hydroxylation of indacaterol. In vitro
investigations further indicated that indacaterol is a low affinity substrate for the efflux pump
P-gp.
Elimination
In clinical studies which included urine collection, the amount of indacaterol excreted
unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol
was, on average, between 0.46 and 1.20 litres/hour. When compared with the serum clearance
of indacaterol of 23.3 litres/hour, it is evident that renal clearance plays a minor role (about 2
to 5% of systemic clearance) in the elimination of systemically available indacaterol.
In a human ADME study where indacaterol was given orally, the faecal route of excretion
was dominant over the urinary route. Indacaterol was excreted into human faeces primarily as
unchanged parent substance (54% of the dose) and, to a lesser extent, hydroxylated

ONB API JUN21 V1.1                                                     Ref EMA SmPC 15Dec2020
indacaterol metabolites (23% of the dose). Mass balance was complete with ≥90% of the dose
recovered in the excreta.
Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal
half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the
accumulation of indacaterol after repeated dosing ranged from 40 to 52 hours which is
consistent with the observed time-to-steady state of approximately 12-14 days.
Special populations
A population pharmacokinetic analysis showed that there is no clinically relevant effect of age
(adults up to 88 years), sex, weight (32 1- 168 kg) or race on the pharmacokinetics of
indacaterol. It did not suggest any difference between ethnic subgroups in this population.
Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax or
AUC of indacaterol, nor did protein binding differ between mild and moderate hepatic
impaired subjects and their healthy controls. Studies in subjects with severe hepatic
impairment were not performed.
Due to the very low contribution of the urinary pathway to total body elimination, a study in
renally impaired subjects was not performed.