Effect of Single and Repeated Doses of Ketoconazole on the ...

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Effect of Single and Repeated Doses of Ketoconazole on thePharmacokinetics of Roflumilast and Roflumilast N-Oxide Gezim Lahu, MSc , Andreas Huennemeyer, MSc, MD , Oliver von Richter, PhD , Robert Hermann, MD , Rolf Herzog , Nigel McCracken, PhD and Karl Zech, PhD
From Nycomed GmbH (formerly ALTANA Pharma AG), Konstanz, Germany(Mr Lahu, Dr Huennemeyer, Mr Herzog, Dr McCracken, Dr von Richter,Dr Zech); University of Tuebingen, Institute for Toxicology,Pharmacy and Chemistry, Tuebingen, Germany (Mr Lahu); and ClinicalResearch Appliance, Radolfzell, Germany (Dr Hermann). Dr vonRichter and Dr Hermann are fellows of the American College ofClinical Pharmacology.
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 ofsingle-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.
Key Words: Drug-drug interactions • healthy subjects • ketoconazole • Phase 1 study • roflumilast
Address for reprints: Gezim Lahu, MSc, Nycomed GmbH, Department ofPharmacometrics and Pharmacokinetics, Byk-Gulden-Str. 2, 78467Konstanz, Germany; e-mail: gezim.lahu{at}nycomed.com .