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

¹ Nycomed GmbH
² Clinical Research Appliance, Radolfzell, Germany

^* To whom correspondence should be addressed. E-mail: gezim.lahu{at}nycomed.com.

	Abstract

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%; 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.
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