Population Pharmacokinetic Analysis of Fluticasone Furoate/Umeclidinium Bromide/Vilanterol in Patients with Chronic Obstructive Pulmonary Disease

Abstract

Background: Population pharmacokinetic methods were used to characterize the pharmacokinetics of fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI) in patients with chronic obstructive pulmonary disease (COPD) when administered as a fixed-dose combination via a single closed inhaler.

Methods: Plasma concentration data from three studies were analyzed using non-linear mixed-effects modeling in NONMEM®.

Results: The pooled dataset consisted of 2948, 2589, and 3331 FF, UMEC, and VI observations from 714, 622, and 817 patients with COPD, respectively. There were 41%, 13%, and 21% of observations below the quantification limit for FF, UMEC, and VI, respectively. The pharmacokinetics of FF, UMEC, and VI were all adequately described by a two-compartment model with first-order absorption. The following covariates were statistically significant, but none were considered to be clinically relevant. For FF, Japanese heritage and FF/VI treatment on apparent inhaled clearance (CL/F) with FF CL/F 35% lower in patients of Japanese heritage across all treatments and FF CL/F 42% higher in patients with COPD following FF/VI administration. This is in line with the product label. For UMEC, weight, age, and smoking status on CL/F and weight on apparent volume of distribution (V2/F) with every 10% increase in age from 60 years of age leading to approximately a 6% decrease in UMEC CL/F and every 10% increase in weight from 70 kg leading to approximately a 6% increase in UMEC CL/F and approximately an 8% increase in UMEC V2/F. For a subject with COPD who smoked, UMEC CL/F was 28% higher. For VI, weight on CL/F and smoking status on V2/F with an approximately 4% increase in VI CL/F for every 10% increase in weight from 70 kg, and for a subject with COPD who smoked, VI V2/F was 46% higher. The majority of these covariates have been previously identified in historical analyses. None of these effects were clinically relevant in terms of systemic exposures and do not warrant dose adjustment.

Conclusions: All FF, UMEC, and VI plasma concentrations were well interspersed with historical data and were all adequately described by a two-compartment model with first-order absorption. There were no clinically relevant differences in FF, UMEC, or VI systemic exposures when administered as FF/UMEC/VI, FF/VI + UMEC, or the dual combinations FF/VI and/or UMEC/VI.

Trial registration: ClinicalTrials.gov NCT02729051 NCT02345161 NCT02164513.

Keywords: COPD; Fluticasone furoate; Population pharmacokinetics; Umeclidinium; Vilanterol.

Conflict of interest statement

Rashmi Mehta, Ruby Birk, Malek Okour, and David A. Lipson are employees of GSK and hold stock in the company. Colm Farrell and Siobhán Hayes are employees of ICON; ICON received funding from GSK to conduct the analysis.

Figures

Fig. 1

Comparison of observed fluticasone furoate (FF) concentration–time data from the present and historical datasets. Open circles represent individual observations; observations reported as below the quantification limit are presented as 0

Fig. 2

Goodness-of-fit plots for the final fluticasone furoate model. Solid black lines represent lines of identity and dashed red lines depict smooth (LOESS) trends

Fig. 3

Visual predictive check for final fluticasone furoate (FF) model. Open circles represent observations; the blue solid line represents the median of simulations; the blue dashed line represents the 95th percentile of simulations; the red line represents the lower limit of quantifications (10 pg/mL); and blue shaded areas represent 90% prediction intervals. The 5th percentile of the simulations was lower limit of quantification for all time points and is not displayed

Fig. 4

Comparison of observed umeclidinium (UMEC) concentration–time data from the present and historical datasets. Open circles represent individual observations; observations reported as below the quantification limit are presented as 0

Fig. 5

Goodness-of-fit plots for the final umeclidinium model. Solid black lines represent lines of identity and dashed red lines depict smooth (LOESS) trends

Fig. 6

Visual predictive check for the final UMEC model. Open circles represent observations; the blue solid line represents the median of simulations; the blue dashed line represents the 5th and 95th percentile of simulations; and the red line represents the lower limit of quantification (10 pg/mL)

Fig. 7

Comparison of observed vilanterol (VI) concentration–time data from the present and historical datasets. Open circles represent individual observations; observations reported as below the quantification limit are presented as 0

Fig. 8

Goodness-of-fit plots for the final vilanterol model. Solid black lines represent lines of identity and dashed red lines depict smooth (LOESS) trends

Fig. 9

Visual predictive check for final vilanterol model. Open circles represent observations; the blue solid line represents the median of simulations; the blue dashed line represents the 5th and 95th percentile of simulations; and the red line represents the lower limit of quantification (10 pg/mL)