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

Chaoying Hu,Jack Peng,Annette Gross,Jingying Jia,Kelly Dong,Rashmi Mehta,Hui Yu,Linda Luo,Yan Ren,Kai Wu,Eng-Huat Tan

doi:10.1371/journal.pone.0121264

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 RegistrationClinicaltrials.gov NCT01899638 NCT01899638

Highlights

Chronic obstructive pulmonary disease (COPD) is a progressive condition characterized by airflow obstruction and reduced maximum expiratory flow, which can lead to restricted activity and poor quality of life.[1]
UMEC was rapidly absorbed with a median tmax of 0.08 h (5 min) following both single- and repeat-dose administration of UMEC with the inhaled LABA vilanterol (UMEC/VI) and UMEC monotherapy (Fig. 2; Table 2)
The results indicated rapid absorption, distribution, and elimination from the systemic circulation of both UMEC and VI

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive condition characterized by airflow obstruction and reduced maximum expiratory flow, which can lead to restricted activity and poor quality of life.[1]. While pharmacokinetic (PK) studies in Western populations have shown that UMEC and VI exhibit low systemic exposure when administered via oral inhalation, PK data in Chinese subjects have not been reported.[12] As inter-ethnic differences in PK have been reported for some drugs, including following oral inhalation, characterization of inhaled UMEC and VI PK in Chinese subjects following oral inhalation is warranted.[13,14] the PK, safety, and tolerability of single and repeat doses of orally inhaled UMEC and VI were assessed in this study, both in combination and as monotherapies, in healthy Chinese subjects

Methods

Results

Conclusion