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No Dose Adjustment on Coadministration of the PDE4 Inhibitor Roflumilast With a Weak CYP3A, CYP1A2, and CYP2C19 Inhibitor: An Investigation Using Cimetidine

This nonrandomized, fixed‐sequence, 2‐period crossover study investigated potential pharmacokinetic interactions between the phosphodiesterase 4 inhibitor roflumilast, currently in clinical development for the treatment of chronic obstructive pulmonary disease, and the histamine 2 agonist cimetidine. Participants received roflumilast, 500 μg once daily, on days 1 and 13. Cimetidine, 400 mg twice daily, was administered from days 6 to 16. Pharmacokinetic analysis of roflumilast and its active metabolite roflumilast N‐oxide was performed, and the ratio of geometric means for roflumilast alone and concomitantly with steady‐state cimetidine was calculated. The effect of cimetidine on the total PDE4 inhibitory activity (tPDE4i; total exposure to roflumilast and roflumilast N‐oxide) was also calculated. Coadministration of steady‐state cimetidine increased mean tPDE4i of roflumilast and roflumilast N‐oxide by about 47%. The maximum plasma concentration (Cmax) of roflumilast increased by about 46%, with no effect on Cmax of roflumilast N‐oxide. The increase in tPDE4i of roflumilast and roflumilast N‐oxide following coadministration with cimetidine was mainly due to the inhibitory effect of cimetidine on cytochrome P450 (CYP) isoenzymes CYP1A2, CYP3A, and CYP2C19. These moderate changes indicate that dose adjustment of roflumilast is not required when coadministered with a weak inhibitor of CYP1A2, CYP3A, and CYP2C19, such as cimetidine.