Investigation of a Potential Food Effect on the Pharmacokinetics of Roflumilast, an Oral, Once-Daily Phosphodiesterase 4 Inhibitor, in Healthy Subjects

This open, randomized, single‐dose crossover study investigated effects of a high‐fat meal on the pharmacokinetics of roflumilast and its major active N‐oxide metabolite. Twelve healthy subjects received oral roflumilast 500 μg (2 × 250 μg) after overnight fasting and after breakfast. Blood was sampled up to 54 hours for pharmacokinetic profiling of roflumilast and N‐oxide. Geometric mean ratios (fed/fasted) for point estimates (PE) and 90% confidence intervals (CI) were calculated for AUC0‐last, AUC0‐∞, and Cmax of both compounds. After the meal, roflumilast Cmax (PE, 0.59; 90% CI, 0.49‐0.70) was modestly reduced; N‐oxide Cmax (PE, 0.95; 90% CI, 0.90‐1.01) was unchanged. Roflumilast tmax was delayed in fed state (2.0 ± 0.4 hours) versus fasted state (1.0 ± 0.2 hours); N‐oxide tmax was unaltered. No significant food effect on roflumilast AUC0‐last (PE, 1.04; 90% CI, 0.90‐1.21), AUC0‐∞ (PE, 1.12; 90% CI, 1.00–1.25), and respective N‐oxide AUCs (PE, 0.91; 90% CI, 0.79‐1.04; PE, 0.99; 90% CI, 0.92‐1.06) occurred. Because roflumilast N‐oxide is the major contributor to roflumilast's overall pharmacologic effects, these findings suggest that roflumilast can be taken with or without food.