10.1177/0091270004264163 ARTICLE HERMANN ET AL INTRANASAL LOTEPREDNOL ETABONATE IN HEALTHY MALES PHARMACOKINETICS AND PHARMACODYNAMICS Intranasal Loteprednol Etabonate in Healthy Male Subjects: Pharmacokinetics and Effects on Endogenous Cortisol Robert Hermann, MD, Mathias Locher, PhD, Marianne Siebert-Weigel, MD, Nicole LaVallee, PhD, Hartmut Derendorf, PhD, FCP, andGünther Hochhaus, PhD, FCP L oteprednol etabonate (LE) is a “soft steroid” that was designed using retrometabolic principles to improve the benefit/risk ratio of topical corticosteroid therapy. 1-3 The approach requires a potent compound with good therapeutic activity at or near the site of appli- cation. In contrast to traditional glucocorticosteroids (GCS), soft steroids are designed to be rapidly inacti- vated upon entering the systemic circulation. Inactiva- tion should be complete and preferably occur either by nonenzymatic degradation or in a single low-energy, high-capacity enzymatic step to minimize unwanted systemic effects. LE was synthesized by chemically modifying an inactive metabolite of prednisolone through addition of a metabolically labile chloromethyl ester group in the 17β-position of the steroid nucleus to confer activity. 4-6 The resulting LE molecule showed topical glucocorticoid action com- parable to that of betamethasone but was nearly de- void of activity in studies that evaluated systemic drug potency. 6-10 510 • J Clin Pharmacol 2004;44:510-519 Loteprednol etabonate (LE) is a glucocorticoid soft drug that is currently in development for intranasal use. The main ob- jectives of this study were to examine the pharmacokinetics and potential effects on systemic cortisol of two intranasal suspension formulations of LE and to compare these findings with placebo and fluticasone propionate (FP, Flonase ® ) con- trol treatments. In this randomized, double-blind (except for FP), parallel-group study (n = 8/group), all subjects received for 14 days once daily in the morning two puffs of the follow- ing nasal spray formulations into each nostril: LE 0.1% (400 μg/day), LE 0.2% (800 μg/day), FP 0.05% (200 μg/day), and placebo. Drug trough levels were determined on days 1, 5, 12, 13, and 14, and a full pharmacokinetic profile was estab- lished on day 14, and 24-hour serum cortisol profiles were as- sessed prior to treatment (i.e., at baseline) and after the last dose. All subjects completed the protocol without treatment- emergent adverse findings. All formulations were rapidly ab- sorbed (t max less than 1 h). The rather short mean terminal half-lives of 2.2 ± 1.5 hours and 1.8 ± 1.0 hours for LE 400 μg and LE 800 μg, respectively, and 4.2 ± 1.8 hours for the 200-μg FP treatment explained the lack of any accumulation. Mean peak concentrations (C max ) were 139 ± 57 pg/mL with LE 400 μg and 164 ± 54 pg/mL with LE 800 μg and thus fairly inde- pendent from dose. The 200-μg FP treatment resulted in a C max of only 15.5 ± 5.9 pg/mL. Mean measured AUC 0-t values (193 ± 87 pg/h/mL –1 , 300 ± 183 pg/h/mL –1 , and 40 ± 34 pg/h/ mL –1 for LE 400 μg, LE 800 μg, and FP 200 μg, respectively) showed high variability and suggested nonlinear pharmacokinetics for the LE formulations, indicative of a less complete systemic uptake of LE from the 0.2% concentration. None of the treatments (LE 400 μg, LE 800 μg, and FP 200 μg) showed evidence for serum cortisol suppression when com- pared with placebo, respectively. The uptake and systemic exposure appears less complete from the 0.2% LE concentra- tion, which principally favors this formulation for further clinical development. Keywords: Loteprednol etabonate; pharmacokinetics; intranasal suspension formulations; endoge- nous cortisol; glucocorticosteroids Journal of Clinical Pharmacology, 2004;44:510-519 ©2004 the American College of Clinical Pharmacology From Clinical Development (Dr. Hermann, Dr. Siebert-Weigel) and Early Phase Development (Dr. Locher), VIATRIS GmbH & Co. KG, Frankfurt am Main, Germany; MURO Pharmaceuticals, Department of Biostatistics, Tewksbury, Massachusetts (Dr. LaVallee); Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida (Dr. Derendorf, Dr. Hochhaus). The study was sponsored by ASTA Medica AG (predecessor of VIATRIS GmbH), Frankfurt am Main, Germany. Submitted for publication November 26, 2003; revised version accepted January 30, 2004. Address for reprints: Günther Hochhaus, PhD, Box 100494, JHMHC, College of Pharmacy, University of Florida, Gainesville, FL 32610-0494. DOI: 10.1177/0091270004264163