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The relationship between fluticasone furoate systemic exposure and cortisol suppression
1Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline R&D, Stevenage, Hertfordshire, SG1 2NY, UK, ann.allen@gsk.com.
Clinical Pharmacokinetics
|May 31, 2013
Summary
This study developed a pharmacokinetic/pharmacodynamic model for fluticasone furoate, showing that high systemic exposure is needed to significantly suppress cortisol levels. The model predicts the exposure required for a 20% reduction in serum cortisol.
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Endocrinology
- Respiratory Medicine
Background:
- Inhaled corticosteroid (ICS) fluticasone furoate is under development for asthma and COPD.
- ICSs can cause dose-dependent systemic effects on the hypothalamic-pituitary-adrenal (HPA) axis, including cortisol suppression.
- 24-h serum and urinary cortisol measurements are sensitive indicators of adrenocortical activity.
Purpose of the Study:
- To characterize the population pharmacokinetic/pharmacodynamic relationship between fluticasone furoate systemic exposure (AUC24) and cortisol levels.
- To assess this relationship in healthy subjects and those with asthma.
Main Methods:
- A meta-analysis of eight studies for serum cortisol and three for urine cortisol was conducted.
- Nonlinear mixed-effect modeling (NONMEM) was used to fit a sigmoid Emax model.
- Fluticasone furoate AUC24, 24-h weighted mean serum cortisol (WM24), and 24-h urine cortisol excretion were analyzed.
Main Results:
- An Emax model effectively described the relationship between fluticasone furoate AUC24 and cortisol suppression.
- The average AUC50 (exposure for 50% max effect) was 1,556 pg·h/mL for serum cortisol and 1,686 pg·h/mL for urine cortisol.
- Age was a significant covariate for urine cortisol, indicating lower excretion in adolescents.
Conclusions:
- A robust pharmacokinetic/pharmacodynamic model for fluticasone furoate and cortisol suppression was established.
- The AUC50 values are substantially higher than those observed at typical clinical doses.
- The model predicts that an AUC24 of 1,000 pg·h/mL would be needed to reduce serum and urine cortisol by 20% and 17%, respectively.
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