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 mu g 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 mu g 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 %; C-max was unchanged. For roflumilast N-oxide, AUC and C-max decreased by 12% and 20%, respectively. Repeated doses of ketoconazole increased the AUC and C-max of roflumilast by 99% and 23%, respectively; for roflumilast N-oxide, AUC was unchanged and C-max decreased by 38%. No clinically relevant adverse events were observed. Coadministration of ketoconazole and roflumilast does not require dose adjustment of roflumilast.