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

Abstract

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 2–4 h for UMEC and 1–2 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 11–34% based on Cmax and 19–59% based on area under the concentration-time curve from time zero to 2 h (AUC(0-2)). VI accumulation following repeat dosing was 25–66% based on Cmax and 17–43% 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.

Conflict of interest statement

Competing Interests: The authors of this manuscript have the following competing interests: KD, LL, KW, RM, JP, YR, AG and HY are employees of GlaxoSmithKline and hold stocks/shares in GlaxoSmithKline. CH and JJ have no conflicts of interest to declare. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Subject disposition.

UMEC, umeclidinium; VI, vilanterol.

Fig 2. Median UMEC plasma concentration—time profiles on Day 1 and Day 10.

LLOQ, lower limit of quantification; PK, pharmacokinetic; UMEC, umeclidinium; VI, vilanterol.

Fig 3. Median VI plasma concentration-time profiles on Day 1 and Day 10.

LLOQ, lower limit of quantification; PK, pharmacokinetic; UMEC, umeclidinium; VI, vilanterol.

Fig 4. Loge-transformed Cmax against weighted mean heart rate (0–4 h) for UMEC (A) and VI (B).

bpm, beats per minute; Cmax, maximum plasma concentration; PK, pharmacokinetic; UMEC, umeclidinium; VI, vilanterol.

Fig 5. Log-transformed Cmax against weighted QTcF (0–4 h) for UMEC (A) and VI (B).

Cmax, maximum plasma concentration; PK, pharmacokinetic; UMEC, umeclidinium; VI, vilanterol.