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

Abstract

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

A Randomized, Crossover Study to Investigate the Pharmacokinetics and Safety of Inhaled Fluticasone Furoate and Umeclidinium, Administered Separately and in Combination via Dry Powder Inhaler in Healthy Adult Volunteers

“…Single-dose studies of UMEC and VI coadministration, and UMEC 10-350 mcg demonstrated rapid UMEC absorption (t max 5-15 min) [16,22]. A t of 1.56 h and 1.78 h has been reported for UMEC 500 mcg alone and UMEC/VI 500/50 mcg, respectively [16], while UMEC 10-350 mcg has demonstrated a mean urine t of 6-10 h [24].…”

“…Extensive data characterizing the safety, pharmacology, and pharmacokinetics (PK) of FF and UMEC were generated in studies in healthy volunteers and patients with asthma and COPD as part of the development program for FF/VI and UMEC/VI [14][15][16][17][18]. To apply these data to guide the development of the FF/UMEC combination, it is necessary to characterize any pharmaceutical and/or PK interactions that result when two active components are administered simultaneously through a single device.…”

Umeclidinium Bromide and Vilanterol Trifenatate Inhalation Powder

“…1,4,7,8,[10][11][12][13][14] There was no difference in vilanterol T max when delivered as monotherapy or in combination. 12 The steady state of umeclidinium/vilanterol is achieved within 14 days, with 1.8-and 1.7-fold accumulation, respectively. 1 However, there is very little increase in maximum serum concentration from days 7 to 14.…”

Vilanterol trifenatate for the treatment of COPD

“…In a single-dose healthy subject Japanese study, UMEC (500µg) and VIL (50µg) monotherapy, and in combination (UMEC/VIL) were reported to have no marked systemic exposures or tolerability issues [21].More recently an open-labeled, randomized, crossover study to assess the pharmacokinetics, safety and tolerability of 2 inhaled UMEC/VIL combinations (62.5/25 and 125/25-µg) compared to their monocomponents (UMEC -62.5 and 125µg; VIL -25µg) in 20 healthy Chinese subjects has been conducted [22]. Following repeat VIL dosing, time to maximum plasma concentration (tmax) was five minutes; with its accumulation at 25-66% of maximum plasma concentration (Cmax) and 17 to 43% based on AUC (0-2).…”