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Effect of Single and Repeated Doses of Ketoconazole on the Pharmacokinetics of Roflumilast and Roflumilast N‐Oxide

Effects of single and multiple doses of oral ketoconazole on roflumilast and its active metabolite, roflumilast N‐oxide, were investigated in healthy subjects. In study 1, subjects (n = 26) received oral roflumilast 500 μg once daily for 11 days and a concomitant 200‐mg single dose of ketoconazole on day 11. In study 2, subjects (n = 16) received oral roflumilast 500 μg on days 1 and 11 and a repeated dose of ketoconazole 200 mg twice daily from days 8 to 20. Coadministration of single‐dose ketoconazole with steady‐state roflumilast increased the AUC of roflumilast by 34%; Cmax was unchanged. For roflumilast N‐oxide, AUC and Cmax decreased by 12% and 20%, respectively. Repeated doses of ketoconazole increased the AUC and Cmax of roflumilast by 99% and 23%, respectively; for roflumilast N‐oxide, AUC was unchanged, and Cmax decreased by 38%. No clinically relevant adverse events were observed. Coadministration of ketoconazole and roflumilast does not require dose adjustment of roflumilast.