Background and objectives: A fixed-dose combination of the bronchodilators umeclidinium and vilanterol is in development for the long-term, once-daily treatment of chronic obstructive pulmonary disease (COPD). We characterized the pharmacokinetics of umeclidinium and vilanterol in ≈1,635 patients with COPD, evaluating the impact of patient demographics and baseline characteristics on umeclidinium and vilanterol exposure.
Methods: Plasma concentrations of umeclidinium and vilanterol were evaluated in patients enrolled in two phase III, randomized, double-blind, parallel-group, placebo-controlled trials using inhaled umeclidinium/vilanterol combination therapy and inhaled umeclidinium and vilanterol monotherapies as treatments. Population-pharmacokinetic models were developed using non-linear mixed-effects analyses, performed using NONMEM(®) software. A likelihood-based approach was used to characterize the data below limit of quantification. Umeclidinium and vilanterol exposures at clinical doses were simulated based on the population model.
Results: For the umeclidinium and vilanterol population-pharmacokinetic analyses, 1,635 and 1,637 patients provided 8,498 and 8,405 observations, respectively. Umeclidinium and vilanterol pharmacokinetics were best described by a two-compartment model with first-order absorption. For umeclidinium, bodyweight, age, and creatinine clearance (CLCR) were statistically significant covariates for apparent inhaled clearance (CL/F); bodyweight was a statistically significant covariate for volume of distribution of central compartment (V 2/F).The population parameter estimates namely CL/F and V 2/F for umeclidinium were 218 L/h and 1,160 L and 40.9 L/h and 268 L for vilanterol. For vilanterol, bodyweight and age were statistically significant covariates for CL/F. The effect of covariates on umeclidinium and vilanterol systemic exposure was marginal. The population model indicates that a 10 % increase in bodyweight will result in a 2 % increase in CL/F for umeclidinium and vilanterol and 6 % increase in umeclidinium V 2/F. A 10 % increase in age will provide a 7 and 4 % decrease in umeclidinium and vilanterol CL/F, respectively. A 10 % decrease in CLCR will result in a 3 % decrease in umeclidinium CL/F. Umeclidinium and vilanterol population-pharmacokinetic model-based systemic exposure predictions showed no pharmacokinetic interactions between umeclidinium and vilanterol when administered in combination.
Conclusions: There were no apparent pharmacokinetic interactions when umeclidinium and vilanterol were co-administered in patients with COPD. The effects of patient demographics, including age, bodyweight, and CLCR, on umeclidinium or vilanterol systemic exposure were minimal, and therefore no dose adjustments are necessary.