Population Pharmacokinetics Modeling of Inhaled Umeclidinium for Adult Patients with Asthma.

Background: Umeclidinium (UMEC; a long-acting anti-muscarinic) in combination with fluticasone furoate (an inhaled corticosteroid) is in development for asthma treatment. This secondary analysis aimed to develop a population pharmacokinetic model characterizing UMEC in adults with asthma, and evaluated the impact of covariates on pharmacokinetic parameters.

Methods: Plasma concentration data from study NCT01641692 (assessing once-daily UMEC 15.6, 31.25, 62.5, 125, and 250 mcg, twice daily UMEC 15.6 and 31.25 mcg, and placebo) were analyzed using non-linear mixed-effect modeling in NONMEM®. Full likelihood, including observed data and data below the quantification limit (treated as censored), was maximized. Study endpoints were population pharmacokinetics (including apparent inhaled clearance [CL/F] and apparent distribution volume in the central compartment [V c/F]) and derived pharmacokinetic parameters (area under the concentration-time curve [AUC] and maximum concentration [C max] at steady-state).

Results: In total, 128 patients provided 3757 data points. The pharmacokinetics of UMEC were best described using a two-compartment model with intravenous bolus input, due to fast absorption following inhalation. CL/F was 257 L/h and V c/F was 804 L. Creatinine clearance was a significant covariate for CL/F, as were age and body weight for V c/F. AUC and C max increased with increasing UMEC dose (once-daily 15.6-250 mcg: AUC0-24 median: 64.7-863 pg h/mL; C max median: 10.6-256 pg/mL).

Conclusions: The final population pharmacokinetic model adequately described the data, demonstrating minimal creatinine clearance, age, and body weight effects on overall plasma UMEC pharmacokinetics and systemic exposure.