Yan Ren and Peiming Ma
Department of Clinical Pharmacology Modelling and Simulation, R&D Shanghai, GlaxoSmithKline, China
Objectives: Fluticasone furoate (FF) is a novel corticosteroid with potent glucocorticoid activity. It has being developed as a potential steroid component in monotherapy and a once daily ICS/LABA combination for asthma and COPD. Cortisol levels in healthy Chinese male subjects before and after FF treatment were measured and characterized by a triple cosine model. The influence of FF on cortisol circadian rhythm was explored.
Methods: In a single centre, double-blind, placebo-controlled, four-way crossover, randomized, single and repeat dose study, FF at different doses (50, 100, 200 mcg) was administered in combination with 25 mcg vilanterol (VI) to evaluate the PK/PD profile, safety and tolerability in healthy Chinese male subjects. A total of 16 healthy subjects aged 18-45 years were randomized with the aim of achieving at least 10 evaluable subjects in each treatment period. Serum cortisol levels were measured on day 7 pre- and 1, 2, 4, 6, 8, 10, 12, 16, 24 hr post FF or placebo repeated dose. Time profiles of cortisol were described by circadian rhythm (cosine) functions.
Results: A model with three cosine terms and baseline could adequately characterize the endogenous cortisol circadian rhythm. Although data were limited (e.g., cortisol was not measured between 10 pm to 8 am), modeling results showed cortisol profiles consistent with results from previous publication [1]. FF concentrations, instead of FF doses, was sufficient when used as a covariate affecting cortisol change using an Emax model.
Conclusions: This cosine model with direct FF effect reasonably captured the circadian rhythm of cortisol in healthy Chinese subjects.
References:
[1] Zhao ZY, Xie Y, Fu YR, Li YY, Bogdan A and Touitou Y. Circadian rhythm characteristics of serum cortisol and dehydroepiandrosterone sulfate in healthy Chinese men aged 30 to 60 years. Steroids 68 (2003) 133-138
Reference: PAGE 23 () Abstr 3313 [www.page-meeting.org/?abstract=3313]
Poster: Drug/Disease modeling - Endocrine