The safety, pharmacokinetics and pharmacodynamics of a combination of fluticasone furoate and vilanterol in healthy Japanese subjects

Nakahara, Norie; Wakamatsu, Akira; Kempsford, Rodger; Allen, Ann; Yamada, Masanori; Nohda, Shigeru; Hirama, Toshiyasu

doi:10.5414/cp201822

Cited by 16 publications

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“…An increased mean absorption time (estimated as the difference between mean residence time following inhaled and intravenous dosing) relative to Caucasians has been observed in East Asian subjects, potentially providing an explanation for the 20–50% higher FF bioavailability . The extent of FF accumulation and the less than dose‐proportional increase of exposures reported in this study are consistent with previously published data in healthy East Asian and Caucasian subjects . VI exposure was similar across the range of coadministered FF/VI doses.…”

Section: Discussionsupporting

confidence: 89%

“…Despite these FF systemic exposure differences, a 22% reduction in serum cortisol level relative to Caucasians was only observed in Japanese but not in Chinese or Korean subjects. In a separate study with FF monotherapy (200, 400, and 800 μg) in healthy Japanese subjects, significant and dose‐dependent serum cortisol level decreases were observed, which clearly correlated with FF systemic exposure (area under the concentration‐time curve from 0 to 24 hours [AUC 0–24 hr ]) . A population PK analysis from global studies has suggested that the maximum observed concentration ( C max ) of VI may be higher in East Asian subjects, compared with non‐Asians, whereas AUC 0–24 hour is consistent across ethnicities .…”

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confidence: 95%

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Pharmacodynamics and Pharmacokinetics of Fluticasone Furoate/Vilanterol in Healthy Chinese Subjects

et al. 2015

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Study ObjectiveTo 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 β2‐agonist for the treatment of asthma and chronic obstructive pulmonary disease – after single and repeat administration in healthy Chinese subjects.DesignDouble‐blind, placebo‐controlled, single‐site, randomized, four‐way crossover study.SettingThe Clinical Pharmacological Research Centre at Peking Union Medical College Hospital [PUMCH]) in Beijing, China.SubjectsSixteen healthy, nonsmoking Chinese adults.InterventionSubjects were randomized to receive FF/VI 50/25, 100/25, or 200/25 μg, 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 ResultsThe 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 β2‐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 μg, respectively, versus placebo. Minor increases (< 10 msec) in maximum QTcF on day 7 were seen with FF/VI 50/25 and 100/25 μg but not with 200/25 μg. Slight decreases in serum potassium level were only observed in subjects receiving FF/VI 50/25 μg on day 1 and FF/VI 50/25 and 200/25 μg on day 7. Fluticasone furoate accumulation (day 7 vs day 1) for FF/VI 50/25–200/25 μg 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.ConclusionIn healthy Chinese subjects, minimal and non–clinically relevant β‐adrenergic pharmacodynamic effects were observed with FF/VI doses ranging from 50/25 to 200/25 μg. FF dose‐dependent reductions in serum cortisol levels of 15–25% were seen after administration of FF/VI 100/25 and 200/25 μg. FF/VI was safe and well tolerated in these subjects at doses ranging from 50/25 to 200/25 μg.

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Section: Discussionsupporting

confidence: 89%

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confidence: 95%

Pharmacodynamics and Pharmacokinetics of Fluticasone Furoate/Vilanterol in Healthy Chinese Subjects

et al. 2015

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“…With 12 subjects, assuming no difference between the treatment groups, it was estimated (based on prior studies [11]) that the lower and upper bounds of the 95% confidence interval (CI) for the difference between test and reference treatments of maximum heart rate (0–4 h) would be within approximately 5.857 bpm of the point estimate.…”

Section: Methodsmentioning

confidence: 99%

Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Umeclidinium and Vilanterol Alone and in Combination: A Randomized Crossover Trial

et al. 2012

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Umeclidinium bromide (GSK573719; UMEC), a new long-acting muscarinic receptor antagonist (LAMA), is in development with vilanterol (GW642444; VI), a selective long-acting β2 agonist (LABA), as a once-daily inhaled combination therapy for the treatment of chronic obstructive pulmonary disease (COPD). A single dose healthy volunteer study was conducted to assess the safety and tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of inhaled umeclidinium (500 µg) and vilanterol (50 µg) when administered separately and in combination using a novel dry powder inhaler (NDPI). Co-administration of single inhaled doses of umeclidinium and vilanterol to healthy Japanese subjects was well tolerated and not associated with meaningful changes in systemic exposure or PD effects compared with administration of either compound individually. Pharmacokinetic assessments showed rapid absorption for both drugs (Tmax = 5 min for both umeclidinium and vilanterol) followed by rapid elimination with median tlast of 4–5 h for umeclidinium and median tlast of 1.5–2.0 h for vilanterol. Assessments of pharmacokinetic interaction were inconclusive since for umeclidinium, Cmax following combination was higher than umeclidinium alone but not AUC whereas for vilanterol, AUC following combination was higher than vilanterol alone but not Cmax. There were no obvious trends observed between individual maximum supine heart rate and umeclidinium Cmax or vilanterol Cmax when delivered as umeclidinium 500 µg and vilanterol 50 µg combination or when delivered as umeclidinium or vilanterol alone.Trial RegistrationClinicaltrials.gov NCT00976144

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“…In separate studies conducted by the same group on the pharmacodynamics in Japanese healthy volunteers of varying doses of monotherapy VIL (12.5, 25 and 50µg), FF (200, 400 and 800µg) and in combination (FF/VIL) (800/50µg) it was reported that there were no safety concerns or treatment-related AEs with repeated dosing of FF and VIL and single doses of FF, VIL and FF/VIL [19]. Systemic exposure to FF and VIL increased in a dose-dependent fashion, with marked serum cortisol reductions after 7-day administration at the highest FF dose of 800µg.…”

Section: Pharmacokinetics Of Vilmentioning

confidence: 99%

Vilanterol trifenatate for the treatment of COPD

Malerba

Radaeli

Montuschi

et al. 2016

Expert Review of Respiratory Medicine

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Introduction: Currently the treatment of chronic obstructive pulmonary disease (COPD) has limited effectiveness and there is a need to develop new drugs. International guidelines recommend the use of long-acting bronchodilators (β2 agonists and anticholinergics/muscarinics), inhaled steroids and associations between these drugs in the maintenance treatment of moderate-to-severe COPD.Area Covered: Vilanterol trifenate is a new once-daily highly selective β2-agonist available in USA and Europe in association with umeclidinium bromide (a long-acting anti-muscarnic agent) and fluticasone furoate (an inhaled corticosteroid) for the once-daily maintenance treatment of COPD.Vilanterol combined in fixed-dose treatments has been tested in numerous clinical trials involving thousands of patients.Expert Commentary: These new once-daily formulations have the potential to improve compliance to long-term inhaled therapy. This paper will review the clinical and experimental data regarding vilanterol use in the regular treatment of COPD as well as provide a critical discussion of possible future treatment settings.

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The safety, pharmacokinetics and pharmacodynamics of a combination of fluticasone furoate and vilanterol in healthy Japanese subjects

Cited by 16 publications

References 0 publications

Pharmacodynamics and Pharmacokinetics of Fluticasone Furoate/Vilanterol in Healthy Chinese Subjects

Pharmacodynamics and Pharmacokinetics of Fluticasone Furoate/Vilanterol in Healthy Chinese Subjects

Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Umeclidinium and Vilanterol Alone and in Combination: A Randomized Crossover Trial

Vilanterol trifenatate for the treatment of COPD

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