PhD student Symbiosis International University, Pune, India
Background: Fluticasone (FP) is a synthetic, trifluorinated glucocorticoid with potent anti-inflammatory activity.1 Following inhaled dosing in healthy volunteers, absolute systemic bioavailability of fluticasone propionate varies between approximately 10- 30% of the nominal dose depending on the inhalation device used.2
Objective: This research focused on a step-by-step procedure to find the population PK models (Pop PK) that best describe the FP concentration data.
This research is considered novel due to the following reasons:
Use of clinically relevant data to build the model
Use of the latest algorithms that can represent complex relationships e.g central versus peripheral lung deposition
Methodology: The Pop PK analysis was conducted using pooled data from 4 studies which included 96 healthy subjects (3860 datapoints). For PopPK model development, the dataset was prepared by combining individual PK data and incorporating covariate information. A nonlinear mixed-effects modeling approach was adopted using ADAPT 5 software (Version 65). The structural model was selected based on model fit criteria. The number of absorptions in the lung was slowly increased with variation in lung absorption with either same ka or different ka.
Covariate screening plots were constructed to explore potential relationships between covariates (e.g., age, weight) and pharmacokinetic parameters. Covariates were tested for their impact on PK parameters, with reduction in the objective function value (OFV) and goodness-of-fit plots serving as criteria for model selection. A decrease of 3.84 points in OFV for one degree of freedom with a p value of < 0.05 was considered a significant improvement of fit.
Results: The 3 compartment (with 2 different absorption rates in the lung; 3cpt2abs) model with first order absorption gave excellent fits for the observed FP concentration after single dosing in healthy subjects. The final model is able to effectively represent the underlying patterns in the observed data, validating its reliability and predictive capacity.
As per the parameter estimates from the final model, it can be concluded as follows:
Approximately, 40% - 50% of fluticasone 1000 mcg inhaled was deposited in the gut and approximately 50%-60% is deposited in the lungs.
< ! There is a lag time before absorption starts in either the central or peripheral lungs.
Conclusion: The PK of fluticasone was adequately described by a linear 3-compartment model with first-order absorption, and an absorption time-lag.
The parameter estimates for lung deposition derived from the final model 3cpt 2abs was consistent with the in vitro estimates of lung deposition. However, further validation of the model is required to reconfirm the findings.
Citations: 1. 1. Chervinsky P, van As A, Bronsky EA, Dockhorn R, Noonan M, LaForce C, Pleskow W. Fluticasone propionate aerosol for the treatment of adults with mild to moderate asthma. The Fluticasone Propionate Asthma Study Group. J Allergy Clin Immunol. 1994 Oct;94(4):676-83.
< !2. Meibohm B, Mollmann H, Wagner M et al. The clinical pharmacology of fluticasone propionate. Rev Contemp Pharmacother 1998;9:535-49.
