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Mometasone Furoate Has Minimal Effects on the Hypothalamic-Pituitary-Adrenal Axis When Delivered at High Doses^*

^* From the Schering-Plough Research Institute (Drs. Affrime, Kosoglou, Thonoor, and Mr. Flannery), Kenilworth, NJ; and Arkansas Research Medical Testing Center (Dr. Herron), Little Rock, AR.

Correspondence to: Melton B. Affrime, PharmD, Schering-Plough Research Institute, 2015 Galloping Hill Rd, K-15–4, 4455, Kenilworth, NJ 07033-0539

Study objectives: To investigate the potential for mometasone furoate (MF) to exert systemic effects following administration by dry powder inhaler (DPI) or metered-dose inhaler (MDI).

Design: Three randomized, evaluator-blind, placebo-controlled, parallel-group, 28-day studies.

Patients: Adults with mild-to-moderate persistent asthma.

Interventions: Study 1 (12 patients per treatment group; MF DPI at 200 µg bid, 400 µg qd, 800 µg qd, or 1,200 µg qd). Study 2 (16 patients per treatment group; MF DPI at 400 µg bid or 800 µg bid, or oral prednisone at 10 mg qd). Study 3 (16 patients per treatment group; MF MDI at 400 µg bid or 800 µg bid, or fluticasone propionate [FP] at 880 µg bid by MDI).

Measurements and results: Study 1. Plasma concentrations were near the lower limit of quantitation (50 pg/mL) at the MF DPI 400-µg qd dosage and approximately 250 pg/mL at the 1,200-µg qd dosage. The area under the curve for serum cortisol concentrations over 24 h (AUC₂₄) was essentially unaltered at all doses. Study 2. Plasma levels over days 7 to 28 were 100.3 ± 5.9 pg/mL (mean ± SEM) for MF DPI 400 µg bid, and 181.0 ± 10.9 pg/mL for 800 µg bid. Although there were relatively low levels of suppression (19 to 25%) at earlier time points for MF DPI 400 µg bid, serum cortisol AUC₂₄ levels at day 28 were similar to placebo. MF DPI 800 µg bid and oral prednisone both decreased serum cortisol AUC₂₄ levels at days 7 to 28 by 28.0 ± 8.3% and 67.2 ± 3.6%, respectively. The response to cosyntropin was normal in 15, 14, 11, and 1 of the patients in the placebo, MF DPI 400 µg bid, MF DPI 800 µg bid, and prednisone groups, respectively. Study 3. MF MDI caused even less systemic exposure than by DPI. MF MDI 800 µg bid (24.0 ± 3.1%) and FP (51.7 ± 3.8%) caused a significant decrease in serum cortisol AUC₂₄ on days 14 to 28. MF MDI 400 µg bid was similar to placebo treatment at all time points.

Conclusions: The MF 800-µg bid dosage (1,600 µg/d), which is twice the highest projected clinical dosage, represents the lower limit for consistently detectable systemic effects of MF.

Key Words: cortisol • fluticasone propionate • hypothalamic-pituitary-adrenal axis • inhaled glucocorticoids • mometasone furoate • prednisone • safety • systemic exposure

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