Understanding Pulmonary and Systemic Pharmacokinetics of Inhaled Fluticasone Propionate in Healthy Subjects Using...

One of the main hurdles in pulmonary drug delivery is the inability to directly quantify drug concentrations at the site of action within the lungs, which are critical for therapeutic efficacy. This research attempted to address this limitation by applying population pharmacokinetic modeling to characterize the pharmacokinetics of fluticasone propionate (FP), integrating multiple pulmonary absorption pathways and identifying key covariates that influence its pharmacokinetics.

Plasma concentration-time data from 96 healthy volunteers participating in four pharmacokinetic (PK) studies using two FP formulations were analyzed, implementing non-linear mixed effects modeling to estimate population pharmacokinetic parameters, including lung deposition-related parameters. In all studies, 1000-µg doses of two FP formulations were administered via a metered-dose inhaler (MDI). A nonlinear mixed effects analysis with a maximum likelihood expectation maximization approach was applied using ADAPT 5 software.

A three-compartment model with first-order distribution, elimination, and absorption processes described the FP pharmacokinetics. The final model considered three absorption peaks, in order of appearance in plasma, presumably in the central and peripheral parts of the lungs, with a delayed peak arising from outside the lung compartments. Weight was a predictor of the apparent clearance and volumes of distribution of FP. The final model suggested that approximately 17% of systemic exposure was associated with drug absorption from the central lung regions, while approximately 14% was associated with absorption from the peripheral lung regions. A secondary delayed peak was observed in the population PK analysis, with the remaining proportion of systemic exposure (~69%) modeled as arising outside the lung compartments. The precise origin of this delayed component remains uncertain, particularly given the extensive first-pass metabolism reported for fluticasone, and may reflect multiple overlapping processes, including redistribution or secondary pulmonary absorption.

The proposed population PK model was able to characterize the PK of FP administered via inhalation and may be useful for better understanding the PK of other drug products administered through the inhalation route.