Dataset Information

Modulation of allergen-induced bronchoconstriction by fluticasone furoate and vilanterol alone or in combination.

ABSTRACT:

Background

This placebo-controlled study assessed the effects of the once-daily inhaled corticosteroid (ICS) fluticasone furoate (FF) and long-acting beta(2) -agonist (LABA) vilanterol (VI) on early and late asthmatic responses (EAR/LAR) and airway hyper-responsiveness (AHR).

Methods

Patients (n = 27) were randomized to FF (100 μg), VI (25 μg), FF/VI (100/25 μg), and placebo for 21 days (four periods). Allergen challenge was performed 1 h post-dose on day 21. AHR was assessed on day 22 using methacholine.

Results

Allergen challenge caused an early change (0-2 h) in minimum forced expiratory volume in 1 s (FEV(1)) of -1.091 l (95% CI: -1.344; -0.837) following placebo therapy; changes were -0.955 l (-1.209; -0.702), -0.826 l (-1.070; -0.581), and -0.614 l (-0.858; -0.370) following VI, FF, or FF/VI therapy, respectively. Treatment differences were significant for all comparisons between therapies. Mean changes in 0-2 h %FEV(1) were as follows: -28.05 (placebo), -23.10 (VI), -22.33 (FF), and -16.10 (FF/VI). Following placebo, the late change (4-10 h) in weighted mean FEV(1) was -0.466 l (-0.589; -0.343) and -0.298 l (-0.415; -0.181) after VI, and was +0.018 l with both FF/VI (-0.089; 0.124) and FF (-0.089; 0.125). Treatment differences were significant for all comparisons between therapies except FF/VI vs FF. Mean changes in 4-10 h %FEV(1) were as follows: -21.08 (placebo), -14.30 (VI), -5.02 (FF), and -5.83 (FF/VI). AHR 24 h after allergen challenge was significantly reduced with FF/VI and FF vs placebo, and FF/VI was superior to either component.

Conclusion

Combined treatment with FF/VI provides additive protection from the EAR relative to its components, significant protection over VI alone from the LAR, and confers sustained protection from hyper-responsiveness 24 h post-dose.

SUBMITTER: Oliver A

PROVIDER: S-EPMC4223930 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:STUDY OBJECTIVE:To investigate the pharmacodynamic and pharmacokinetic profiles of fluticasone furoate (FF)/vilanterol (VI) - a fixed-dose combination of an inhaled corticosteroid (ICS) and a long-acting ?2 -agonist for the treatment of asthma and chronic obstructive pulmonary disease - after single and repeat administration in healthy Chinese subjects. DESIGN:Double-blind, placebo-controlled, single-site, randomized, four-way crossover study. SETTING:The Clinical Pharmacological Research Centre at Peking Union Medical College Hospital [PUMCH]) in Beijing, China. SUBJECTS:Sixteen healthy, nonsmoking Chinese adults. INTERVENTION:Subjects were randomized to receive FF/VI 50/25, 100/25, or 200/25 ?g, or placebo once/daily in the morning, delivered by the Ellipta dry powder inhaler, for 7 consecutive days. The subjects then received the other three treatments, with each treatment period separated by a 7-day washout period. MEASUREMENTS AND MAIN RESULTS:The co-primary outcome measures reflected pharmacodynamic responses relating to recognized class effects of the two drug classes: reduced serum cortisol level (ICSs), and increased Fridericia's corrected QT interval (QTcF) and reduced serum potassium level (long-acting ?2 -agonists). Co-primary pharmacodynamic endpoints were 0-24-hour weighted mean serum cortisol level on day 7 (cortisol0-24 hr, Day 7 ), and 0-4-hour weighted mean and maximum QTcF and weighted mean and minimum serum potassium level on days 1 and 7. Fluticasone furoate and VI plasma concentrations, derived pharmacokinetic parameters, and safety were also assessed. Of the 16 subjects randomized, 15 completed the study. Reductions in cortisol0-24 hour, Day 7 of 15% and 25% were observed with FF/VI 100/25 and 200/25 ?g, respectively, versus placebo. Minor increases (< 10 msec) in maximum QTcF on day 7 were seen with FF/VI 50/25 and 100/25 ?g but not with 200/25 ?g. Slight decreases in serum potassium level were only observed in subjects receiving FF/VI 50/25 ?g on day 1 and FF/VI 50/25 and 200/25 ?g on day 7. Fluticasone furoate accumulation (day 7 vs day 1) for FF/VI 50/25-200/25 ?g ranged from 38 to 54% for maximum observed concentration and 63-71% for area under the concentration-time curve from 0 to 4 hours. Fluticasone furoate pharmacokinetics were less than dose proportional. The VI pharmacokinetic profiles were similar for all three FF/VI doses. Adverse events were all mild in intensity and were reported by 13 (81%) of the 16 subjects. CONCLUSION:In healthy Chinese subjects, minimal and non-clinically relevant ?-adrenergic pharmacodynamic effects were observed with FF/VI doses ranging from 50/25 to 200/25 ?g. FF dose-dependent reductions in serum cortisol levels of 15-25% were seen after administration of FF/VI 100/25 and 200/25 ?g. FF/VI was safe and well tolerated in these subjects at doses ranging from 50/25 to 200/25 ?g.

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