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Intranasal Loteprednol Etabonate in Healthy Male Subjects: Pharmacokinetics and Effects on Endogenous Cortisol

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).

Loteprednol etabonate (LE) is a glucocorticoid soft drug that is currently in development for intranasal use. The main objectives 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®) control 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 following 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 established on day 14, and 24-hour serum cortisol profiles were assessed 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 absorbed (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 independent 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 compared with placebo, respectively. The uptake and systemic exposure appears less complete from the 0.2% LE concentration, which principally favors this formulation for further clinical development.

Key Words: Loteprednol etabonate • pharmacokinetics • intranasal suspension formulations • endogenous cortisol • glucocorticosteroids

Address for reprints: Günther Hochhaus, PhD, Box 100494, JHMHC, College of Pharmacy, University of Florida, Gainesville, FL 32610-0494.

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