Pharmacokinetics and tolerability of inhaled umeclidinium and vilanterol alone and in combination in healthy Chinese subjects: a randomized, open-label, crossover trial.

UNLABELLED: Inhaled umeclidinium (UMEC) and the combination of inhaled UMEC with vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease in the US and EU. This was a randomized, open-label, three-period crossover, single- and repeat-dose study to assess the pharmacokinetics (PK), safety, and tolerability of inhaled UMEC/VI 62.5/25 µg (delivering 55/22 µg) and UMEC/VI 125/25 µg (delivering 113/22 µg) compared with their monotherapy components (UMEC 62.5 µg, UMEC 125 µg and, VI 25 µg [delivering 55, 113, and 22 µg, respectively]) in healthy Chinese subjects (n=20). UMEC and VI were rapidly absorbed following single and repeat dosing (time to maximum plasma concentration [tmax]: UMEC = 5 min; VI = 5 min). The median tlast was 2­4 h for UMEC and 1­2 h for VI following single doses of UMEC/VI and UMEC monotherapy (both doses). UMEC reached steady-state prior to Day 10; steady-state for VI could not be assessed. UMEC accumulation following repeat dosing was 11­34% based on Cmax and 19­59% based on area under the concentration-time curve from time zero to 2 h (AUC(0-2)). VI accumulation following repeat dosing was 25­66% based on Cmax and 17­43% based on AUC(0-2). The evidence was not sufficient to suggest that systemic exposure was substantially different between UMEC/VI combination therapy and the constituent monotherapies following single or repeat dosing. Following both single- and repeat-dose administration, the inter-subject coefficient of variation for all UMEC PK parameter estimates ranged from 12% to 165% for all treatments, indicating a wide range of variability in inhaled PK parameters. Twelve subjects experienced ≥1 adverse event (AE). Six subjects experienced ≥1 treatment-related AE; the most commonly reported treatment-related AE was chest discomfort (n=3 [15%]). No clinically important changes in vital signs or electrocardiogram parameters were reported. These data suggest that single- and repeat-dose administration of UMEC/VI combination therapy in healthy Chinese subjects did not result in substantial differences in systemic exposure compared with UMEC and VI as monotherapies. TRIAL REGISTRATION: Clinicaltrials.gov NCT01899638 NCT01899638.