Nicolas Simon, Eliane Fuseau, Peter Daley-Yates
GlaxoWellcome, Clinical Pharmacology - Full Development, Greenford UK
Seretide is a combination of Salmeterol (50pg) with Fluticasone propionate (500pg) administered twice daily by inhalation for treatment of asthma. A population pharmacokinetic analysis was performed to compare the pharmacokinetics of fluticasone propionate (500pg strength) alone or administered with salmeterol (50pg) concurrently or as a combination product (3 arms). In a full-scale phase III study to compare the efficacy and safety of the 3 treatments, forty-two adult patients with a documented clinical history of reversible airways obstruction were included in a pharmacokinetic screen. After 12 weeks of dosing, a full pharmacokinetic profile was obtained with the following sample-times: pre-dose, 1, 2, 3, 4 and 10 hours. A one- compartment model and first-order absorption best fitted the pharmacokinetic data. The covariates investigated were age, weight, sex, FEVI and cortisol. A gender effect was found both on distribution volume/F and on clearance/F: males had a 31% higher clearance/F and distribution volume/F than female subjects. This result is likely related to a difference in lung deposition (F) between males and females. Indeed, females had a higher percent predicted FEVI (at time of sampling) than males, 88.3 and 71.2% respectively (p<0.01). The concurrent treatment group showed an apparent decrease of distribution volume/F (28%) resulting in slightly higher Cmax compared to the 2 other treatments. None of these effects would require dose adjustment. Age and weight did not affect fluticasone propionate pharmacokinetics. The clinical study showed that the combination product were equivalent for the efficacy and safety study end-points. The PK/PD model of Mishina et al. (1998) combined with patients PK data will be used to predict plasma cortisol concentrations in asthma patients.
Reference:
Mishina EV, Miller R, Falcoz C. PK/PD population model linking cortisol production with fluticasone concentration. 99th annual meeting of American Society for Clinical Pharmacology and Therapeutics, April 1, 1998, New Orleans, Louisiana USA.
Reference: PAGE 7 () Abstr 687 [www.page-meeting.org/?abstract=687]
Poster: poster