Population Pharmacokinetics of Inhaled Fluticasone Furoate and Vilanterol in Subjects with Chronic Obstructive Pulmonary Disease.

Background and Objectives: Previous pharmacokinetic studies of the inhaled corticosteroid, fluticasone furoate (FF), and the long-acting, beta2-receptor agonist, vilanterol (VI) have been performed in relatively small populations using non-compartmental pharmacokinetic methods and censored data (due to low drug exposure relative to assay sensitivity). This paper presents a population pharmacokinetic analysis, utilizing pooled concentration-time data from clinical studies in healthy subjects and from global trials in patients with chronic obstructive pulmonary disease (COPD). The objective of this analysis was to characterize the population pharmacokinetics of FF and VI following once-daily inhalation dosing of FF/VI or the individual components (FF and VI) and to identify significant covariates that impact systemic exposure to FF and VI in this population.
Methods: Population pharmacokinetic methods that maximize the likelihood of all data were developed to describe systemic exposure to FF and VI following once-daily FF/VI, FF, or VI, and to identify significant covariates that impact the pharmacokinetics. COPD patients (N = 1225 for the FF analysis and N = 1091 for the VI analysis; 94 and 93 % of total data, respectively) and healthy subjects contributed to the analysis.
Results: FF data were described by a two-compartment model with first-order absorption and elimination. The population grouping "race" was a significant covariate on inhaled clearance (CL/F). The area under the curve over 24 h (AUC _0-24 ) for FF was higher for East Asian, Japanese, and South East Asian (average 23-30 %) and Asian Central, White Arabic, American Indian/Native Alaskan, and 'other' (10-26 %) subjects compared with White/Caucasians. VI pharmacokinetics were described by a three-compartment model with zero-order absorption and first-order elimination. Significant demographic covariates identified to affect pharmacokinetics of VI were age [on CL/F and central volume (V ₁ /F)], bodyweight (on CL/F), sex and smoking (on V ₁ /F).
Conclusions: While significant effects of the covariates were observed in this study, the magnitude of these effects on systemic exposure is not large enough to warrant FF/VI dosage adjustment in patients with COPD.
Competing Interests: Compliance with Ethical Standards Funding All of the studies used in this analysis were funded by GSK. Conflict of interest Sarah Siederer and Shuying Yang are employed by and hold shares in GSK. Ann Allen was an employee of GSK at the time of these analyses. Ethical approval All procedures were carried out in accordance with the International Conference on Harmonisation E6 guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki. The studies described in this paper were approved by independent institutional review boards and ethics committees at all study sites. A full list of approving bodies is included in Appendix 1. Informed consent Written informed consent was obtained from each subject prior to the performance of any study-specific procedures.