Request Copyright Permission

Fluticasone Pharmacokinetics: Meta-Analysis and Models

Sakagami M.

Respiratory Drug Delivery 2014. Volume 1, 2014: 143-154.

Abstract:

Inhaler- and formulation-dependent variations in pharmacokinetic (PK) profiles for inhaled fluticasone propionate (FP) and fluticasone furoate (FF) have been suggested as a means of detecting clinical differences between products, and thus as a potential tool to assess bioequivalence (BE). A meta-analysis of their PK profiles from the literature appeared to indicate rate-controlled lung absorption that was slower than the systemic distribution kinetics, likely due to slow dissolution in the airways. A new kinetic model incorporating terms describing lung-regional aerosol deposition (dose-to-lung, DTL, and DTL fraction deposited in the peripheral lung, Fdepp), alongside dissolution rate-controlled lung absorption (first-order rate constant for dissolution, kdiss) was developed and used to analyze the clinical PK profiles from the literature for inhaled FP and FF following the use of different inhalers. Given appropriate DTL values, the model was successful in curve-fitting each of the PK profiles in healthy subjects with a kdiss value of about 0.2 h-1 for both inhaled FP and FF. The use of typical cascade impactor data to estimate DTL values, however, appeared to require caution, since the PK profiles differed substantially within and between inhalers in spite of reports of comparable in vitro aerodynamic particle size distribution (APSD) data. The model also enabled the effects of lung dose, regional deposition and dissolution on likely changes in PK profiles to be simulated. The results are discussed in the light of the current debate on the use of PK studies to assess BE of orally inhaled drug products (OIDPs).