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

Abstract

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.

Pharmacokinetics of Single and Repeat Doses of Fluticasone Furoate/Umeclidinium/Vilanterol in Healthy Chinese Adults

“…This contrasts with findings from a previous trial of FF monotherapy (Arnuity ELLIPTA), which showed that FF was increased in Chinese patients (C max , 181 pg/mL) compared with Caucasian patients (C max , 118 pg/mL); however, the FF dose used was higher than in the current study (200–800 vs 100 µg). The C max for FF 100 µg in the present study was also higher following repeat doses (day 7) than following a single dose (day 1), similar to findings from a previous trial of FF/VI (Relvar Breo ELLIPTA) in Chinese subjects …”

“…At day 1, the overall systemic exposure of FF 100 µg in this study was low (C max , 10.46 pg/mL). Previous studies of FF PK following FF/VI (100/25 µg) administration (Relvar Breo ELLIPTA) in Chinese participants demonstrated higher day 1 exposure (C max , 26.8 pg/mL) . The differences in FF exposure are unlikely to be from variations in body weight because these values were similar to those in the current study.…”

“…Results from a PK study of UMEC/VI (Anoro ELLIPTA) and the constituent monotherapies showed that the PK profile in Chinese patients was consistent with previous studies in Caucasian populations . In contrast, PK studies of inhaled FF monotherapy and FF/VI dual therapy (Relvar/Breo ELLIPTA) demonstrated higher systemic FF exposures in Chinese patients compared with Caucasian patients . The difference in exposures could be accounted for, in part, by differences in body size, rather than hepatic metabolism, because CYP3A4 was shown to have similar activity in Caucasian and Chinese patients .…”

“…Inhaled FF has been shown to exhibit time‐independent PK with rate‐limiting absorption from the lung . FF exposures in healthy Chinese subjects over the dose range of 50–200 µg once daily increased in a less‐than‐dose‐proportional manner . For UMEC and VI, PKs were approximately dose‐proportional and time‐invariant over the dose ranges studied, with low oral bioavailability in healthy volunteers .…”

Spotlight on fluticasone furoate/vilanterol trifenatate for the once-daily treatment of asthma: design, development and place in therapy

“…Pharmacodynamic, pharmacokinetic and safety data have been tested with inhaled FF/VI in several populations, including healthy Chinese and Japanese, in patients simultaneously on ketoconazole and in patients with renal and hepatic impairment 22–25. Stable pharmacokinetics and pharmacodynamics and no safety concerns over the use of inhaled FF/VI were found in these studies.…”