Foster Mechanism of Action

Pharmacotherapeutic Group: Adrenergics and other drugs for obstructive airway diseases. ATC Code: R03 AK08.
Pharmacology: Pharmacodynamics: Mechanisms of action and pharmacodynamics effects: Foster contains beclometasone dipropionate and formoterol. These two actives have different modes of action. In common with other inhaled corticosteroids and beta₂-agonist combinations, additive effects are seen in terms of reduction of asthma exacerbations.
Beclometasone dipropionate: Beclometasone dipropionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma with less adverse effects than when corticosteroids are administered systemically.
Formoterol: Formoterol is a selective beta₂-adrenergic agonist that produces relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect sets in rapidly, within 1-3 minutes after inhalation, and has a duration of 12 hours after a single dose.
Asthma: Clinical efficacy for Foster maintenance therapy: In clinical trials in adults, the addition of formoterol to beclometasone dipropionate improved asthma symptoms and lung function and reduced exacerbations.
In a 24-week study the effect on lung function of Foster was at least equal to that of the free combination of beclometasone dipropionate and formoterol, and exceeded that of beclometasone dipropionate alone.
Clinical efficacy for Foster maintenance and reliever therapy: In a 48-week parallel group study involving 1701 asthma patients, the efficacy of Foster administered as maintenance (1 inhalation BID) and reliever therapy (up to a total of 8 puffs per day) was compared to Foster administered as maintenance therapy (1 inhalation BID) plus as needed salbutamol, in adult patients with un-controlled moderate to severe asthma. The results demonstrated that Foster used as maintenance and reliever therapy significantly prolonged the time to first severe exacerbation (*) when compared with Foster used as maintenance plus as needed salbutamol (p< 0.001 for both ITT and PP population). The rate of severe asthma exacerbations per patients/year, was significantly reduced in the maintenance and reliever therapy group compared to salbutamol group: 0.1476 vs 0.2239 respectively (statistically significant reduction: p<0.001). Patients in the Foster maintenance and reliever group achieved a clinically meaningful improvement in asthma control. The mean number of inhalations/day of reliever medication and the proportion of patients using reliever medication decreased similarly in both groups.
Note*: severe exacerbations were defined as deterioration in asthma resulting in hospitalisation or emergency room treatment, or resulting in the need for systemic steroids for more than 3 days.
In another clinical study, a single dose of FOSTER 100/6 mcg provided a quick bronchodilation effect and a rapid relief from dyspnea symptoms similar to that of salbutamol 200 mcg/dose in asthmatic patients when metacholine challenge is used to induce bronchoconstriction.
COPD: In two 48-weeks studies, the effects on lung function and the rate of exacerbation (defined as courses of oral steroids and/or course of antibiotics and/or hospitalisations) in patients with severe COPD (30%<FEV₁%<50%) was evaluated.
One pivotal trial showed a significant improvement in lung function (primary endpoint change in pre-dose FEV₁) compared to formoterol after 12 weeks of treatment (adjusted mean difference between Foster and formoterol: 69 ml) as well as at each clinic visit during the whole treatment period (48 weeks). The study demonstrated that the mean number of exacerbations per patient/year (exacerbation rate, co-primary endpoint) was statistically significantly reduced with Foster as compared with formoterol treatment (adjusted mean rate 0.80 compared with 1.12 in the formoterol group, adjusted ratio 0.72, p <0.001) over 48 weeks treatment period in a total of 1199 patients with severe COPD. In addition, Foster statistically significantly prolonged the time to first exacerbation compared to formoterol. The superiority of Foster versus formoterol was also confirmed in terms of exacerbation rate in subgroups of patients taking (around 50% in each treatment arm) or not Tiotropium Bromide as concomitant medication.
The other pivotal study, which was a three arm, randomised, parallel group study in 718 patients, confirmed the superiority of Foster versus formoterol treatment in terms of change in pre-dose FEV₁ at the end of treatment (48 weeks) and demonstrated the non-inferiority of Foster compared to budesonide/formoterol fixed dose combination on the same parameter.
Pharmacokinetics: The systemic exposure to the active substances beclometasone dipropionate and formoterol in the fixed combination Foster have been compared to the single components.
In a pharmacokinetic study conducted in healthy subjects treated with a single dose of Foster fixed combination (4 puffs of 100/6 micrograms) or a single dose of beclometasone dipropionate CFC (4 puffs of 250 micrograms) and Formoterol HFA (4 puffs of 6 micrograms), the AUC of beclometasone dipropionate main active metabolite (beclometasone-17-monopropionate) and its maximal plasma concentration were, respectively, 35% and 19% lower with the fixed combination than with non-extrafine beclometasone dipropionate CFC formulation, in contrast, the rate of absorption was more rapid (0.5 vs 2h) with the fixed combination compared to non-extrafine beclometasone dipropionate CFC formulation alone.
For formoterol, maximal plasma concentration was similar after administration of the fixed or the extemporary combination and the systemic exposure was slightly higher after administration of Foster than with the extemporary combination.
There was no evidence of pharmacokinetic or pharmacodynamic (systemic) interactions between beclometasone dipropionate and formoterol.
The use of Aerochamber Plus spacer increased the lung delivery of beclometasone dipropionate active metabolite beclometasone 17-monopropionate and formoterol of 41% and 45% respectively, in comparison to the use of standard actuator in a study conducted in healthy volunteers. The total systemic exposure was unchanged for formoterol, reduced by 10% for beclometasone 17-monopropionate and increased for unchanged beclometasone dipropionate.
A lung deposition study conducted in stable COPD patients, healthy volunteers and asthmatic patients, demonstrated that on average 33% of the nominal dose is deposited into the lung of COPD patients compared to 34% in healthy subjects and 31% in asthmatic patients. Beclometasone 17-monopropionate and formoterol plasma exposures were comparable across the three groups during the 24 hours following the inhalation. The total exposure of beclometasone dipropionate was higher in COPD patients compared to the exposure in asthmatic patients and healthy volunters.
Beclometasone dipropionate: Beclometasone dipropionate is a pro-drug, with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclometasone-17-monopropionate, which has a more potent topical anti-inflammatory activity compared with the pro-drug beclometasone dipropionate.
Absorption, distribution and biotransformation: Inhaled beclometasone dipropionate is rapidly absorbed through the lungs; prior to absorption there is extensive conversion to its active metabolite beclometasone-17-monopropionate via esterase enzymes that are found in most tissues. The systemic availability of the active metabolite arises from lung (36%) and from gastrointestinal absorption of the swallowed dose. The bioavailability of swallowed beclometasone dipropionate is negligible, however, pre-systemic conversion to beclometasone-17-monopropionate results in 41% of the dose being absorbed as the active metabolite.
There is an approximately linear increase in systemic exposure with increasing inhaled dose.
The absolute bioavailability following inhalation is approximately 2% and 62% of the nominal dose for unchanged beclometasone dipropionate and beclometasone-17-monopropionate respectively.
Following intravenous dosing, the disposition of beclometasone dipropionate and its active metabolite are characterised by high plasma clearance (150 and 120L/hr, respectively), with a small volume of distribution at steady state for beclometasone dipropionate (20L) and larger tissue distribution for its active metabolite (424L).
Plasma protein-binding is moderately high.
Elimination: Faecal excretion is the major route of beclometasone dipropionate elimination mainly as polar metabolites. The renal excretion of beclometasone dipropionate and its metabolites is negligible. The terminal elimination half-lives are 0.5 h and 2.7 h for beclometasone dipropionate and beclometasone-17-monopropionate respectively.
Special populations: The pharmacokinetics of beclometasone dipropionate in patients with renal or hepatic impairment has not been studied; however, as beclometasone dipropionate undergoes a very rapid metabolism via esterase enzymes present in intestinal fluid, serum, lungs and liver, to originate the more polar products beclometasone-21-monopropionate, beclometasone-17-monopropionate and beclometasone, hepatic impairment is not expected to modify the pharmacokinetics and safety profile of beclometasone dipropionate.
As beclometasone dipropionate or its metabolites were not traced in the urine, an increase in systemic exposure is not envisaged in patients with renal impairment.
Formoterol: Absorption and distribution: Following inhalation, formoterol is absorbed both from the lung and gastrointestinal tract. The fraction of an inhaled dose that is swallowed after administration with a metered dose inhaler (MDI) may range between 60% and 90%. At least 65% of the fraction that is swallowed is absorbed from the gastrointestinal tract. Peak plasma concentrations of unchanged drug occur within 0.5 to 1 hours after oral administration. Plasma protein binding of formoterol is 61-64% with 34% bound to albumin. There was no saturation of binding in the concentration range attained with therapeutic doses. The elimination half-life determined after oral administration is 2-3 hours. Absorption of formoterol is linear following inhalation of 12 to 96 μg of formoterol fumarate.
Biotransformation: Formoterol is widely metabolised and the prominent pathway involves direct conjugation at the phenolic hydroxyl group. Glucuronide acid conjugate is inactive. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Cytochrome P450 isoenzymes CYP2D6, CYP2C19 and CYP2C9 are involved in the O-demethylation of formoterol. Liver appears to be the primary site of metabolism. Formoterol does not inhibit CYP450 enzymes at therapeutically relevant concentrations.
Elimination: The cumulative urinary excretion of formoterol after single inhalation from a dry powder inhaler increased linearly in the 12 - 96 μg dose range. On average, 8% and 25% of the dose was excreted as unchanged and total formoterol, respectively. Based on plasma concentrations measured following inhalation of a single 120 μg dose by 12 healthy subjects, the mean terminal elimination half-life was determined to be 10 hours. The (R,R)- and (S,S)-enantiomers represented about 40% and 60% of unchanged drug excreted in the urine, respectively. The relative proportion of the two enantiomers remained constant over the dose range studied and there was no evidence of relative accumulation of one enantiomer over the other after repeated dosing.
After oral administration (40 to 80 μg), 6% to 10% of the dose was recovered in urine as unchanged drug in healthy subjects; up to 8% of the dose was recovered as the glucuronide.
A total of 67% of an oral dose of formoterol is excreted in the urine (mainly as metabolites) and the remainder in the faeces. The renal clearance of formoterol is 150 ml/min.
Special populations: Hepatic/Renal impairment: the pharmacokinetics of formoterol has not been studied in patients with hepatic or renal impairment. However, as formoterol is primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver cirrhosis.
Toxicology: Preclinical Safety Data: The toxicity observed in animal studies with beclometasone dipropionate and formoterol, given in combination or separately, consisted mainly of effects associated with exaggerated pharmacological activity. They are related to the immuno-suppressive activity of beclometasone dipropionate and to the known cardiovascular effects of formoterol evident mainly in dogs. Neither increase in toxicity nor occurrence of unexpected findings were observed upon administration of the combination.
Reproduction studies in rats showed dose-dependent effects. The combination was associated with reduced female fertility and embryofetal toxicity. High doses of corticosteroids to pregnant animals are known to cause abnormalities of fetal development including cleft palate and intra-uterine growth retardation, and it is likely that the effects seen with the beclometasone dipropionate/formoterol combination were due to beclometasone dipropionate. These effects were noted only with high systemic exposure to the active metabolite beclometasone-17-monopropionate (200 fold the expected plasma levels in patients). Additionally, increased duration of gestation and parturition, an effect attributable to the known tocolytic effects of beta₂-sympathomimetics, was seen in animal studies. These effects were noted when maternal plasma formoterol levels were below the levels expected in patients treated with Foster.
Genotoxicity studies performed with a beclometasone dipropionate/formoterol combination do not indicate mutagenic potential. No carcinogenicity studies have been performed with the proposed combination. However animal data reported for the individual constituents do not suggest any potential risk of carcinogenicity in man.
Pre-clinical data on the CFC-free propellant HFA-134a reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.