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 β(2) 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 registration: Clinicaltrials.gov NCT00976144.

Conflict of interest statement

Competing Interests: DK, RM, BJF, AP, JB and GC are full time employees and own stock in GlaxoSmithKline. PT was a contract medical monitor employed by GlaxoSmithKline during this study. Editorial support (in the form of writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing) was provided by Gloria Boone M.S., M.BA. and Lawrence Boone Ph.D., Boone Consulting Services, Fuquay Varina, North Carolina, United States of America and was funded by GlaxoSmithKline. GlaxoSmithKline has patents and patent applications that cover umeclidinium, vilanterol and the combination of umeclidinium and vilanterol. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. CONSORT diagram.

Figure 2. Pharmacodynamic analyses.

(a) Analysis of derived blood potassium parameters. (b) Plot of adjusted means FEV1 time profile.

Figure 3. Plot of individual maximum (0–4 h) HR versus Cmax.

(a) Umeclidinium log Cmax. (b) Vilanterol log Cmax.