Relvar Ellipta Mechanism of Action

Corticosteroid/Selective Long-acting beta₂-adrenergic Agonist.
Pharmacology: Pharmacodynamics: Mechanism of action: Fluticasone furoate and vilanterol represent two classes of medications (a synthetic corticosteroid and a selective, long-acting beta₂-receptor agonist).
Pharmacodynamic effects: Fluticasone furoate: Fluticasone furoate is a synthetic trifluorinated corticosteroid with potent anti inflammatory activity. The precise mechanism through which fluticasone furoate affects asthma and COPD symptoms is not known. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g. eosinophils, macrophages, lymphocytes) and mediators (e.g. cytokines and chemokines involved in inflammation).
Vilanterol trifenatate: Vilanterol trifenatate is a selective long-acting, beta₂-adrenergic agonist (LABA).
The pharmacologic effects of beta₂-adrenoceptor agonist drugs, including vilanterol trifenatate, are at least in part attributable to stimulation of intracellular adenylate cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
Molecular interactions occur between corticosteroids and LABAs, whereby steroids activate the beta₂-receptor gene, increasing receptor number sensitivity; and LABAs prime the glucocorticoid receptor for steroid-dependent activation and enhance cell nuclear translocation. These synergistic interactions are reflected in enhanced anti-inflammatory activity, which has been demonstrated in vitro and in vivo in a range of inflammatory cells relevant to the pathophysiology of both asthma and COPD. Airway biopsy studies have also shown the synergy between corticosteroids and LABAs to occur at clinical doses of the drugs in patients with COPD.
Clinical Studies: Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) clinical studies: Asthma: The safety and efficacy of fluticasone furoate (FF) and vilanterol (VI) in the treatment of asthma has been evaluated in 3 randomised, double-blind clinical trials of between 12 to 76 weeks in duration (HZA106827, HZA106829 and HZA106837) involving 3,210 patients 12 years of age and older with persistent asthma.
All subjects were using an ICS (Inhaled Corticosteroid) with or without LABA for at least 12 weeks prior to Visit 1. In HZA106837 all patients had at least one exacerbation that required treatment with oral corticosteroids in the year prior to Visit 1. Results for HZA106827 and HZA106829 are shown in the table as follows: (See Table 1.)

Click on icon to see table/diagram/image

HZA106837 was of variable treatment duration (from a minimum of 24 weeks to a maximum of 76 weeks with the majority of patients treated for at least 52 weeks) and compared Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 micrograms [N=1009] and FF 100 micrograms [N=1010]. The primary endpoint was the time to first severe asthma exacerbation (a severe asthma exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroids or an inpatient hospitalization or emergency department visit.
The risk of experiencing a severe asthma exacerbation in patients receiving Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 was reduced by 20% compared with FF 100 alone (hazard ratio 0.795, p=0.036 95% CI (0.642, 0.985)). The rate of severe asthma exacerbations per patient per year was 0.19 in the FF 100 group and 0.14 in the Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 group. The ratio of the exacerbation rate for Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 versus FF 100 was 0.755 (95% CI 0.603, 0.945). This represents a 25% reduction in the rate of severe asthma exacerbations for subjects treated with Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 compared with FF 100 (p=0.014). The 24-hour bronchodilator effect of Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) was maintained throughout a one-year treatment period with no evidence of loss in efficacy (no tachyphylaxis). Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 micrograms consistently demonstrated 83 mL to 95 mL improvements in trough FEV₁ at Weeks 12, 36 and 52 and Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 group were well controlled (ACQ7 ≤0.75) at end of treatment compared to 36% of subjects in the FF 100 group (p<0.001 95% CI 1.23, 1.82).
Chronic Obstructive Pulmonary Disease: The efficacy of fluticasone furoate and vilanterol in the treatment of patients with COPD has been evaluated in two 6-month (HZC112206, HZC112207) and two one-year randomised controlled studies (HZC102970, HZC102871) in patients with a clinical diagnosis of COPD.
Six month studies: HZC112206 and HZC112207 were 24 week randomised, double-blind, placebo controlled, parallel group studies comparing the effect of the combination to vilanterol and FF alone and placebo. HZC112206 evaluated the efficacy of Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 50/25 micrograms [n=206] and Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 micrograms [n=206]) compared with FF (100 micrograms [n=206]) and vilanterol (25 micrograms [n=205]) and placebo (n=207), all administered once daily.
HZC112207 evaluated the efficacy of Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 micrograms [n=204] and Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 200/25 [n=205]) compared with FF (100 micrograms [n=204] and 200 micrograms [n=203]) and vilanterol (25 micrograms [n=203]) and placebo (n=205), all administered once daily.
The co-primary endpoints in both studies were the weighted mean FEV₁ from zero to 4 hours post-dose and change from baseline in pre-dose trough FEV₁ at the end of the study.
In an integrated analysis of both studies, Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 micrograms showed clinically meaningful improvements in lung function. At the 24-week time point Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 micrograms and vilanterol increased trough FEV₁ by 129 mL (95% CI 91, 167 mL, p<0.001) and 83 mL (95% CI 46, 121 mL, p<0.001) respectively compared with placebo. Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 micrograms increased trough FEV₁ by 46 ml compared with vilanterol (95% CI 8, 83 mL, p=0.017).
At the 24-week time point Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 micrograms and vilanterol had a higher weighted mean FEV₁ over 0-4 hours of 193 mL (95% CI 156, 230 mL, p<0.001) and 145 mL (95% CI 108, 181 mL, p<0.001) respectively compared with placebo. The difference in weighted mean FEV₁ over 0-4 hours between the fluticasone furoate/vilanterol 100/25 and vilanterol groups was 48 (95 CI 12, 84 mL, p=0.009).
12 months studies: Studies HZC102970 and HZC102871 were 52 week randomised, double-blind, parallel-group, studies comparing the efficacy and safety of Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 200/25 micrograms, Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 micrograms, fluticasone furoate/vilanterol 50/25 micrograms and vilanterol 25 micrograms, all administered once daily. The primary endpoint was the reduction in the annual rate of moderate and severe exacerbations in subjects with COPD.
The results of both studies showed that treatment with Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 micrograms once daily resulted in a 27% reduction in the annual rate of moderate or severe COPD exacerbations compared with vilanterol (95% CI:16, 37 mL (p≤0.001). Similar reductions in the time to first exacerbation and exacerbations requiring systemic corticosteroid use were observed with fluticasone furoate/vilanterol 100/25 micrograms once daily.
In a pooled analysis of HZC102970 and HZC102871, at Week 52, the Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) 100/25 microgram group demonstrated greater improvement in trough FEV₁ compared with the vilanterol 25 microgram group (a difference of 42 mL in adjusted mean change from baseline; 95% CI: 19, 64 mL, p<0.001).
Pharmacokinetics: Absorption: The absolute bioavailability for fluticasone furoate and vilanterol when administered by inhalation as Fluticasone furoate + Vilanterol (as trifenatate) (Relvar Ellipta) was on average 15.2% and 27.3%, respectively. The oral bioavailability of both fluticasone furoate and vilanterol was low, on average 1.26% and <2%, respectively. Given this low oral bioavailability, systemic exposure for fluticasone furoate and vilanterol following inhaled administration is primarily due to absorption of the inhaled portion of the dose delivered to the lung.
Distribution: Following intravenous dosing, both fluticasone furoate and vilanterol are extensively distributed with average volumes of distribution at steady state of 661 L and 165 L, respectively.
Both fluticasone furoate and vilanterol have a low association with red blood cells. In vitro plasma protein binding in human plasma of fluticasone furoate and vilanterol was high, on average >99.6% and 93.9%, respectively. There was no decrease in the extent of in vitro plasma protein binding in subjects with renal or hepatic impairment.
Fluticasone furoate and vilanterol are substrates for P-gp, however, concomitant administration of fluticasone furoate/vilanterol with P-gp inhibitors is considered unlikely to alter fluticasone furoate or vilanterol systemic exposure since they are both well absorbed molecules.
Metabolism: Based on in vitro data, the major routes of metabolism of both fluticasone furoate and vilanterol in human are mediated primarily by CYP3A4.
Fluticasone furoate is primarily metabolised through hydrolysis of the S-fluoromethyl carbothioate group to metabolites with significantly reduced corticosteroid activity.
Vilanterol is primarily metabolised by O-dealkylation to a range of metabolites with significantly reduced β₁- and β₂-agonist activity.
A repeat dose CYP3A4 drug interaction study was performed in healthy subjects with the fluticasone furoate/vilanterol combination (200/25) and the strong CYP3A4 inhibitor ketoconazole (400 mg). Co-administration increased mean fluticasone furoate AUC_(0-24) and C_max by 36% and 33%, respectively. The increase in fluticasone furoate exposure was associated with a 27% reduction in 0-24 h weighted mean serum cortisol.
Co-administration increased mean vilanterol AUC_(0-t) and C_max 65% and 22%, respectively. The increase in vilanterol exposure was not associated with an increase in beta-agonist related systemic effects on heart rate, blood potassium or QTcF interval.
Elimination: Following oral administration, fluticasone furoate was eliminated in humans mainly by metabolism with metabolites being excreted almost exclusively in faeces, with <1% of the recovered radioactive dose eliminated in the urine. The apparent plasma elimination half-life of fluticasone furoate following inhaled administration of fluticasone furoate/vilanterol was, on average, 24 hours.
Following oral administration, vilanterol was eliminated in humans mainly by metabolism followed by excretion of metabolites in urine and faeces approximately 70% and 30% of the radioactive dose respectively. The apparent plasma elimination half-life of vilanterol following inhaled administration of fluticasone furoate/vilanterol was, on average, 2.5 hours.
Special Patient Populations: Population PK meta-analyses for fluticasone furoate and vilanterol were conducted in phase III studies in subjects with asthma or COPD. The impact of demographic covariates (age, gender, weight, BMI, racial group, ethnicity) on the pharmacokinetics of fluticasone furoate and vilanterol were evaluated as part of the population pharmacokinetic analysis.
Race: In subjects with asthma or COPD estimates of fluticasone furoate AUC_(0-24) for East Asian, Japanese and South East Asian subjects (12-14% subjects) were up to 53% higher on average compared with Caucasian subjects. However, there was no evidence for the higher systemic exposure in these populations to be associated with greater effect on 24 hour urinary cortisol excretion. There was no effect of race on pharmacokinetic parameter estimates of vilanterol in subjects with COPD.
On average, vilanterol C_max is estimated to be 220 to 287% higher and AUC_(0-24) comparable for those subjects from an Asian heritage compared with subjects from other racial groups. However, there was no evidence that this higher vilanterol C_max resulted in clinically significant effects on heart rate.
Children: In adolescents (12 years or older), there are no recommended dose modifications.
The pharmacokinetics of fluticasone furoate/vilanterol in patients less than 12 years of age has not been studied. The safety and efficacy of fluticasone furoate/vilanterol in children under the age of 12 years has not yet been established.
Elderly: The effects of age on the pharmacokinetics of fluticasone furoate and vilanterol were determined in phase III studies in COPD and asthma.
There was no evidence for age (12-84) to affect the PK of fluticasone furoate and vilanterol in subjects with asthma.
There was no evidence for age to affect the PK of fluticasone furoate in subjects with COPD while there was an increase (37%) in AUC_(0-24) of vilanterol over the observed age range of 41 to 84 years. For an elderly subject (aged 84 years) with low bodyweight (35 kg) vilanterol AUC_(0-24) is predicted to be 35% higher than the population estimate (subject with COPD aged 60 years and bodyweight of 70 kg), whilst C_max was unchanged. These differences are unlikely to be of clinical relevance.
Renal impairment: A clinical pharmacology study of fluticasone furoate/vilanterol showed that severe renal impairment (creatinine clearance <30mL/min) did not result in significantly greater exposure to fluticasone furoate or vilanterol or more marked corticosteroid or beta₂-agonist systemic effects compared with healthy subjects. No dose adjustment is required for patients with renal impairment.
The effects of haemodialysis have not been studied.
Hepatic Impairment: Following repeat dosing of fluticasone furoate/vilanterol for 7 days, there was an increase in fluticasone furoate systemic exposure (up to three-fold as measured by AUC_(0-24)) in subjects with hepatic impairment (Child-Pugh A, B or C) compared with healthy subjects The increase in fluticasone furoate systemic exposure (fluticasone furoate/vilanterol 200/25 micrograms) in subjects with moderate hepatic impairment (Child-Pugh B) was associated with an average 34% reduction in serum cortisol compared with healthy subjects. In subjects with severe hepatic impairment (Child Pugh C) that received a lower dose of 100/12.5 micrograms there was no reduction in serum cortisol. For patients with moderate or severe hepatic impairment the maximum dose is 100/25 micrograms (see Dosage & Administration).
Following repeat dosing of fluticasone furoate/vilanterol for 7 days, there was no significant increase in systemic exposure to vilanterol (C_max and AUC) in subjects with mild, moderate, or severe hepatic impairment (Child-Pugh A, B or C).
There were no clinically relevant effects of the fluticasone furoate/vilanterol combination on beta-adrenergic systemic effects (heart rate or serum potassium) in subjects with mild or moderate hepatic impairment (vilanterol, 25 micrograms) or with severe hepatic impairment (vilanterol, 12.5 micrograms) compared with healthy subjects.
Gender, Weight and BMI: There was no evidence for gender, weight or BMI to influence the pharmacokinetics of fluticasone furoate based on a population pharmacokinetic analysis of phase III data in 1213 subjects with asthma (712 females) and 1225 subjects with COPD (392 females).
There was no evidence for gender, weight or BMI to influence the pharmacokinetics of vilanterol based on a population pharmacokinetic analysis in 856 subjects with asthma (500 females) and 1091 subjects with COPD (340 females).
No dosage adjustment is necessary based on gender, weight or body mass index (BMI).
Toxicology: Pre-clinical Safety Data: Pharmacological and toxicological effects seen with fluticasone furoate or vilanterol in nonclinical studies were those typically associated with either glucocorticoids or beta₂-agonists. Administration of fluticasone furoate combined with vilanterol did not result in any significant new toxicity.
Carcinogenesis/mutagenesis: Fluticasone furoate was not genotoxic in a standard battery of studies and was not carcinogenic in lifetime inhalation studies in rats or mice at exposures similar to those at the maximum recommended human dose, based on AUC.
Genetic toxicity studies indicate vilanterol does not represent a genotoxic hazard to humans. Consistent with findings for other beta₂-agonists, in lifetime inhalation studies vilanterol caused proliferative effects in the female rat and mouse reproductive tract and rat pituitary gland. There was no increase in tumour incidence in rats or mice at exposures 2- or 30-fold, respectively, those at the maximum recommended human dose, based on AUC.
Reproductive Toxicology: Effects seen following inhalation administration of fluticasone furoate in combination with vilanterol in rats were similar to those seen with fluticasone furoate alone.
Fluticasone furoate was not teratogenic in rats or rabbits, but delayed development in rats and caused abortion in rabbits at maternally toxic doses. There were no effects on development in rats at exposures approximately 3-times greater than those at the maximum recommended human dose, based on AUC.
Vilanterol was not teratogenic in rats. In inhalation studies in rabbits, vilanterol caused effects similar to those seen with other beta₂-agonists (cleft palate, open eyelids, sternebral fusion and limb flexure/malrotation). When given subcutaneously there were no effects at exposures 84-times greater than those at the maximum recommended human dose, based on AUC.
Neither fluticasone furoate nor vilanterol had any adverse effects on fertility or pre- and post-natal development in rats.