The relationship between systemic exposure to fluticasone propionate and cortisol reduction in healthy male volunteers

Objective: The aim of this analysis was to assess the pharmacokinetic/pharmacodynamic relationship between systemic exposure to fluticasone propionate (FP) and reductions in the plasma cortisol level and urinary cortisol excretion. Methods: A total of 122 healthy male volunteers participating in 7 different studies received either oral (5 to 40mg), inhaled (500 to 2000 mug) or intravenous (250 to 1000 mug) single morning doses of FP or placebo. Data on systemic exposure to FP, expressed in terms of the area under the FP concentration-time curve up to 24 hours (AUC(24h,FP)) for the 3 different routes of administration were pooled, together with corresponding data on the 24-hour plasma cortisol level or urinary cortisol excretion. The data were used to develop a pharmacokinetic/pharmacodynamic model, from which parameter estimates and 95% confidence intervals (CI) for the estimates could be derived. Results: The intercept in the absence of drug (E-0) was -0.5% (95% CI: -0.6, -0.3%) and the maximum drug-induced reduction in mean plasma cortisol levels (E-max was 72% (95% CI: 64, 79%). The systemic exposure to FP that resulted in half the maximum possible reduction in plasma cortisol levels (AUC(50)) was 3.2 mug/L . h (95% CI: 2.8, 3.7 mug/L . h); this equates approximately to the plasma FP concentration obtained after administration of a 1000 mug inhaled dose. A similar relationship was seen between AUC(50) and urinary cortisol excretion, although the variability in AUC(50) for urinary cortisol was much greater than for plasma cortisol. Conclusion: A pharmacokinetic/pharmacodynamic model has been established which relates systemic exposure to FP (after a single morning dose) to the percentage reduction in urinary or plasma cortisol. The relationship is independent of both dose and route of administration.