High absolute bioavailability of the new oral phosphodiesterase-4 inhibitor roflumilast

OBJECTIVE: To establish basic intravenous (IV) pharmacokinetics of roflumilast (ROF) and its pharmacologically active metabolite roflumilast N-oxide (R-NO) and to determine the absolute bioavailability of ROF in humans. MATERIALS: In a randomized, open-label, 2-period, 2-sequence crossover study 12 healthy male subjects were randomized to receive ROF either orally (PO) 500 µg (immediate release tablets) or single IV (150 µg over 15 min). Plasma concentrations were determined. Dose-adjusted point estimates and 90% confidence intervals (CI) were calculated for the ratio of the AUC time curves using a multiplicative model and parametric analysis. RESULTS: After IV administration, clearance of ROF was 0.14 l/h/kg, volume of distribution (Vd area) 2.92 l/kg, and the terminal t1/2 was 14.8 h. After PO administration, ROF was rapidly absorbed; the absolute bioavailability was 79%. The AUC of the R-NO metabolite generally exceeded that of ROF. After IV and PO administration, the metabolic ratios were 7.4 and 12.4, respectively. Dose-adjusted analysis of the R-NO AUC values indicate a 21% higher R-NO formation seen with PO vs. IV, suggesting entire first-pass conversion of ROF is to the active R-NO. Formation/clearance processes of the R-NO appear to be slow with an observed tmax of 6.9 - 8.8 h, and corresponding to apparent t1/2 values of 22.7 h and 20.6 h, after IV and PO administration, respectively. CONCLUSION: ROF is rapidly absorbed after PO administration and exhibits high absolute bioavailability and low clearance pharmacokinetics. The total exposure of R-NO exceeds that of ROF by a factor of 12 after oral administration.