Population Pharmacokinetic Modeling of Fluticasone Furoate, Umeclidinium Bromide, and Vilanterol in Patients with Asthma, Using Data from a Phase IIIA Study (CAPTAIN).

BACKGROUND

This analysis aimed to characterize the pharmacokinetics (PK) of the inhaled corticosteroid (ICS) fluticasone furoate (FF), the long-acting muscarinic antagonist umeclidinium (UMEC), and the long-acting β2-agonist (LABA) vilanterol (VI), administered as dual (FF/VI) or triple (FF/UMEC/VI) single-inhaler therapy to patients with asthma, and to identify covariates that may influence the PK of each analyte.

METHODS

Blood samples were obtained from the phase IIIA CAPTAIN study (ClinicalTrials.gov: NCT02924688), which evaluated the efficacy and safety of once-daily FF/UMEC/VI versus FF/VI in patients with uncontrolled asthma taking ICS/LABA. Samples were collected at trough (defined as ≥ 20 h after the last dose) from all subjects randomized to the six treatment groups (FF/UMEC/VI 100/31.25/25 μg, 100/62.5/25 μg, 200/31.25/25 μg, 200/62.5/25 μg; FF/VI 100/25 μg, 200/25 μg) at week 24 or the early withdrawal visit. In a subset of patients, PK samples were obtained predose at week 12, and at 5-30 min, 45-90 min, and 2-3 h postdose. For each analyte, a population PK model was developed using non-linear mixed-effects modeling. The maximum likelihood method was utilized to incorporate data below the quantifiable limit (BQL). Final models were used to derive the area under the plasma concentration-time curve and maximum observed concentration at steady-state for each analyte.

RESULTS

We obtained 4018, 2695, and 4032 samples from 1891, 1258, and 1891 patients, for FF, UMEC, and VI, respectively; 48%, 49%, and 50% of samples were reported as BQL for each analyte, respectively. The PK were adequately described by a two-compartment model with first-order absorption and elimination for FF, a two-compartment model with intravenous bolus input and first-order elimination for UMEC, and a three-compartment model with zero-order input and first-order elimination for VI. Statistically significant covariates were body weight on apparent inhaled clearance of FF, creatinine clearance on apparent clearance and body weight on apparent inhaled volume of distribution of the central compartment for UMEC, and race (East Asian, Japanese, and South East Asian heritage) on inhaled apparent volume of distribution of the central compartment for VI. However, the overall effects of covariates were marginal and thus do not warrant dose adjustment. Systemic exposures of FF or VI did not differ when administered as a single-inhaler triple (FF/UMEC/VI) or dual combination (FF/VI), and were similar to those reported for patients with chronic obstructive pulmonary disease.

CONCLUSION

Only marginal covariate effects were observed, and thus no dose adjustments are deemed necessary for FF, UMEC, or VI. There was no difference in FF or VI systemic exposure in patients with asthma when administered as either triple (FF/UMEC/VI) or dual therapy (FF/VI). Together with efficacy findings from the CAPTAIN study, our data support the use of single-inhaler FF/UMEC/VI triple therapy for patients with uncontrolled asthma currently receiving ICS/LABA.