The Relationship between Systemic Exposure to Fluticasone Propionate and Cortisol Reduction in Healthy Male Volunteers
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Clin Pharmacokinet 2000; 39 Suppl. 1: 47-54 0312-5963/00/0001-0047/$20.00/0 © Adis International Limited. All rights reserved.
The Relationship between Systemic Exposure to Fluticasone Propionate and Cortisol Reduction in Healthy Male Volunteers Alison E. Mackie1 and Alan Bye2 1 Lilly Research Centre Limited, Windlesham, Surrey, England 2 Clinical Pharmacology, Glaxo Wellcome Research and Development, Greenford, Middlesex, England
Abstract
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 2000μg) or intravenous (250 to 1000μg) 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 (AUC24h,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 (E0) was –0.5% (95% CI: –0.6, –0.3%) and the maximum drug-induced reduction in mean plasma cortisol levels (Emax) was 72% (95% CI: 64, 79%). The systemic exposure to FP that resulted in half the maximum possible reduction in plasma cortisol levels (AUC50) was 3.2 μg/L • h (95% CI: 2.8, 3.7 μg/L • h); this equates approximately to the plasma FP concentration obtained after administration of a 1000μg inhaled dose. A similar relationship was seen between AUC50 and urinary cortisol excretion, although the variability in AUC50 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.
The ideal glucocorticoid for the topical treatment of asthma should have potent anti-inflammatory activity in the lungs and produce minimal systemic effects, such as a reduction in plasma cortisol
levels. Fluticasone propionate (FP) was designed to have a high topical-to-systemic activity ratio;[1] this was achieved by virtue of its potency and high systemic clearance. Inhaled FP is effective in the
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treatment of asthma at the recommended dosage of 50 to 1000μg twice daily.[2] The pharmacokinetic profile of FP has been established in healthy volunteers after administration by the intravenous, inhaled and oral routes. The elimination kinetics of FP after intravenous administration are linear, indicating that metabolism of the drug is not saturated over the inhaled therapeutic dosage range.
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