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A3029 - Population Pharmacokinetic Analysis of Single Inhaler Triple Therapy (ICS/LAMA/LABA) Versus Dual Therapy (LAMA/LABA and ICS/LABA) in Patients with Symptomatic COPD: Combined Results from Three Phase III Trials
Author Block: R. Mehta1, C. Farrell2, S. Kilbride3, C. Zhu3, J. Brooks4, F. Barnhart1, R. Birk3, D. A. Lipson5; 1GSK, Durham, NC, United States, 2ICON Development Solutions, Marlow, United Kingdom, 3GSK, Uxbridge, United Kingdom, 4GSK, King of Prussia, PA, United States, 5GSK, King Of Prussia, PA, United States.
Rationale: The pharmacokinetics (PK) of fluticasone furoate (FF), umeclidinium (UMEC) and vilanterol (VI) have been characterized thoroughly in patients with chronic obstructive pulmonary disease (COPD) when administered as monotherapy and the dual-combinations FF/VI and UMEC/VI but not as the triple-combination FF/UMEC/VI. Methods: Three phase III, randomised, double-blind, parallel group, studies evaluated single-inhaler triple therapy with FF/UMEC/VI (100/62.5/25 µg) versus dual-combination or ‘open-triple’ (FF/VI + UMEC) therapies in patients aged ≥40 years with COPD who were at risk of exacerbation. POP-PK models for FF, UMEC and VI were developed using NONMEM® software. A likelihood-based approach accounted for plasma samples with drug concentrations below the limit of quantification. Demographic and baseline characteristic data were evaluated as covariates to determine any effect on FF, UMEC and VI pharmacokinetic parameters. Goodness-of-fit plots, visual predictive checks, objective function value, parameter precision were used for model selection. Area under the curve (AUC) and maximum observed concentration (Cmax) for FF/UMEC/VI (via a single ELLIPTA® inhaler) were derived and compared with once-daily FF/VI and UMEC/VI from IMPACT and historical data for once-daily FF/VI (RELVAR or BREO ELLIPTA®) and UMEC/VI (ANORO ELLIPTA®). Results: Final FF, UMEC and VI population pharmacokinetic (PK) datasets from combined IMPACT, FULFIL, and study 200812 contained 2948, 2589 and 3331 plasma concentration-time data from 714, 622 and 817 subjects, respectively, with 21-41% samples below limit of quantification. FF, UMEC and VI PK were all adequately described by a two-compartment model with first-order absorption. For FF, Japanese heritage and FF/VI treatment were significant covariates on apparent inhaled clearance. For both UMEC and VI, weight and age were significant covariates on apparent inhaled clearance. Smoking status was a significant covariate on UMEC inhaled apparent volume and VI inhaled apparent clearance, POP-PK analyses demonstrated that the effects of these covariates on PK were marginal and no dose adjustment was deemed necessary for FF, UMEC or VI based on these covariates. Steady state AUCss (geometric mean, pg*h/mL) and Cmax ss (geometric mean, pg/mL) for FF/UMEC/VI were consistent with historical data for FF/VI and UMEC/VI. Conclusions: Population PK analysis for FF/UMEC/VI using combined data from IMPACT, FULFIL and study 200812 were consistent with those for the components when given in dual combination. The models described adequately the PK of FF, UMEC and VI in patients with COPD. No dose adjustments are warranted based on age, weight, smoking status or race. Funding source: GSK (IMPACT: NCT02164513/CTT116855; FULFIL: NCT2345161/CTT116853; study 200812: NCT02729051/CTT200812)