British Journal of Clinical Pharmacology
DOI:10.1111/j.1365-2125.2007.02919.x
Pharmacokinetic/pharmacodynamic evaluation of urinary cortisol suppression after inhalation of fluticasone propionate and mometasone furoate Zia R. Tayab, Tom C. Fardon,1 Daniel K. C. Lee,1 Kay Haggart,1 Lesley C. McFarlane,1 Brian J. Lipworth1 & Günther Hochhaus Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA and 1Asthma and Allergy Research Group, Department of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, UK What is already known about this subject • Mometasone furoate (MF) is a new inhaled glucocorticoid for which the first reports suggested a low degree of systemic side-effects and low systemic availability. • Recent studies of Fardon and colleagues have shown that MF’s cortisol suppression is similar to that of fluticasone. • Pharmacokinetic/dynamic evaluations of MF’s systemic side-effects, probing whether systemic side-effects can be explained by systemic availability, plasma protein binding and receptor binding affinity, are lacking in the literature. Correspondence Günther Hochhaus, PhD, PO Box 100494, Department of Pharmaceutics, College of Pharmacy, JHMHC, University of Florida, Gainesville, FL 32610, USA. Tel: + 1 352 846 2727 Fax: + 1 352 392 4447 E-mail:
[email protected]
Aim Fluticasone propionate (FP) and mometasone furoate (MF) are inhaled corticosteroids that possess a high ratio of topical to systemic activity. The systemic bioavailability of MF has been claimed to be minimal (1%). FP has been shown to exhibit the same degree of systemic effects, but its systemic availability is between 13 and 17%. We hypothesize that FP and MF have comparable systemic availabilities that can explain their potential to cause systemic effects. Methods Steady-state FP and MF trough plasma samples were determined from a clinical study by Fardon et al. in patients with persistent asthma (forced expiratory volume in 1 s = 91%). The percent plasma protein binding of FP and MF was measured using ultracentrifugation. Free FP plasma concentrations were normalized for their differences in receptor binding affinity compared with MF and linked to overnight urinary cortisol/creatinine with an inhibitory Emax.
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Keywords fluticasone propionate, mometasone furoate, plasma protein binding, pulmonary deposition, systemic side-effects
Results A plot of steady-state FP and MF total trough plasma concentrations vs. dose showed that both drugs exhibit dose linearity. MF has comparable bioavailability to FP based on the steady-state concentrations observed for the different doses. The free plasma concentration producing 50% of urinary cortisol suppression (IC50) for MF was not statistically different from the free, normalized IC50 for FP.
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Received 12 September 2006 Accepted 23 February 2007 Published OnlineEarly 17 May 2007
Br J Clin Pharmacol
64:5
What this study adds • This study shows that the systemic availability of MF and fluticasone propionate (FP) are similar and that systemic availability is directly related to the dose. • It also shows that the metabolites of MF are present only in very low concentrations at most, contrary to results in rats. • The observed cortisol suppression of FP and MF is related to the trough plasma concentrations and seems to be in agreement with its observed systemic availability, plasma protein binding and receptor binding affinity.
Conclusion FP and MF have similar pulmonary deposition and the same potential to cause systemic side-effects due to their similar IC50 values. The observed urinary cortisol suppression of FP and MF is in agreement with their systemic availability, their differences in plasma protein binding and receptor binding affinity.
698–705
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© 2007 The Authors Journal compilation © 2007 Blackwell Publishing Ltd
Short report
Introduction
Asthma is a chronic inflammatory disorder of the airways that affects nearly 150 million people worldwide [1]. Since their introduction nearly 30 years ago, inhaled corticosteroids have become the mainstay of treatment for chronic asthma [2–4]. Although given locally into the lung, inhaled glucocorticoids can induce systemic side-effects, which can include skin thinning, easy bruising, decreased bone density, growth retardation and adrenal suppression [5–7]. Due to these unwanted effects, there have been efforts to improve further the safety profile of inhaled glucocorticoids. One of the newest inhaled glucocorticoids is mometasone furoate (MF), a halogenated glucocorticoid with a high lipophilicity as well as a high affinity for the glucocorticoid receptor, low systemic absorption and high metabolic clearance [8–11]. MF is available for use in allergic rhinitis in the USA [12, 13] and is approved for asthma therapy in Europe. At the time of the submission of this paper, it is being investigated for asthma therapy in the USA. The relative binding affinity (RBA) of MF to the glucocorticoid receptor is higher than that of fluticasone propionate (FP), while its clearance is similar to that of other inhaled glucocorticoids [12, 14, 15]. Given the higher affinity and higher potency of MF compared with FP, it would seem logical to assume that similar doses of MF would lead to a greater degree of unwanted sideeffects. However, early reports [16] have indicated that cortisol suppression of MF is negligible and that the low systemic bioavailability of 1%, compared with 13–17% for FP [9, 17, 18] and/or the high plasma protein binding (99% for MF [19] and 90% for FP [9, 20, 21]), could be the reason. Fardon et al. [10], compared the overnight urinary cortisol/creatinine concentrations after administration of low, medium and high doses of MF and FP at steady state. The authors found that at medium and high doses of FP and MF there was significant suppression of overnight urinary cortisol concentrations corrected for creatinine clearance [10]. The goal of this study was to evaluate whether systemic side-effects observed in the Fardon study are in agreement with observed plasma concentrations, receptor binding affinity and plasma protein binding of FP and MF. Methods Study design
Parts of this study, namely the effects of MF and FP on urinary cortisol, have been previously published by Fardon et al. [10]. The present study extends the results by evaluating the plasma concentrations of MF and FP
and correlating these with the observed effects on urinary cortisol. In the original study by Fardon et al. [10], 22 patients with mild to moderate asthma [age range 23–67 years (mean 48 ⫾ 13)] were assigned to two treatment groups. The first group received FP with an Accuhaler dry powder device at 250 mg twice a day for 2 weeks. This would be followed by 500 mg twice a day for 2 weeks and then 1000 mg twice daily for 2 weeks. After each 2-week treatment period, a urinary cortisol/creatinine measurement would be taken along with a corresponding plasma sample (for MF and FP measurements), 12 h after the last dose. The patients would then be subjected to a 1-week wash-out period where they were given 50 mg salmeterol twice a day and 10 mg montelukast once a day. After the wash-out period, the patients were given MF with a Twisthaler dry powder device at 200 mg twice a day for 2 weeks. This was followed by 400 mg twice a day for 2 weeks and then 800 mg twice a day for 2 weeks. A plasma sample and corresponding urinary cortisol measurement were taken after each 2-week treatment period. The other group of patients were given the same doses, but in the reverse order.
Analysis of FP and MF plasma samples
FP was purchased from Sigma-Aldrich (St Louis, MO, USA). MF was obtained from USP (Rockville, MD, USA), 6b-hydroxy MF was a gift from Professor P. Högger (Institut für Pharmazie und Lebensmittelchemie, Würzburg, Germany) and 13C3-fluticasone propionate was provided by GSK R&D (Ware, UK). Highperformance liquid chromatography grade solvents were purchased from Fisher chemicals (Springfield, NJ, USA) and solid-phase LC18 cartridges for solid-phase extraction were acquired from Supelco (Bellafonte, PA, USA). Drug-free human plasma was purchased from the Civitan regional blood system (Gainesville, FL, USA). FP and MF trough plasma samples from the clinical study conducted by Fardon and coworkers [10] were quantified with liquid chromatography tandem mass spectrometry (LC-MS-MS) after solid-phase extraction as previously described [22]. Surprisingly, low plasma concentrations were found in placebo samples. This might be due to patients being exposed to FP- or MF-contaminated air in the clinic, as such levels were not determined in relevant calibration and quality control samples. For 6b-hydroxy MF, the MF method was adapted by using a transition m/z 537–501. The limit of quantification for FP was 15 pg ml-1, 45 pg ml-1 for MF and 200 pg ml-1 for 6b-hydroxy MF. Br J Clin Pharmacol
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Plasma protein binding determination
Samples of FP and MF were prepared in three different batches of human drug-free plasma by spiking in a stock solution of drug in methanol into plasma to concentrations of 10, 50 and 150 ng ml-1 to a total volume of 5 ml. The concentration of methanol in plasma was
