Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects |
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Authors: | Nassr Nassr,reas Huennemeyer,Rolf Herzog,Oliver von Richter,Robert Hermann,Manuela Koch,Kevin Duffy,Karl Zech,& Gezim Lahu |
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Affiliation: | Nycomed GmbH, Konstanz,;Clinical Research Appliance, Radolfzell,;AAI Pharma Deutschland GmbH &Co. KG, Neu-Ulm and;University of Tübingen, Institute for Pharmacy, Tübingen, Germany |
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Abstract: | AIMSTo evaluate the effect of co-administration of rifampicin, an inducer of cytochrome P450 (CYP)3A4, on the pharmacokinetics of roflumilast and roflumilast N-oxide. Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor, being developed for the treatment of chronic obstructive pulmonary disease. Roflumilast is metabolized by CYP3A4 and CYP1A2, with further involvement of CYP2C19 and extrahepatic CYP1A1. In vivo, roflumilast N-oxide contributes >90% to the total PDE4 inhibitory activity.METHODSSixteen healthy male subjects were enrolled in an open-label, three-period, fixed-sequence study. They received a single oral dose of roflumilast 500 µg on days 1 and 12 and repeated oral doses of rifampicin 600 mg once daily on days 5–15. Plasma concentrations of roflumilast and roflumilast N-oxide were measured for up to 96 h. Test/Reference ratios and 90% confidence intervals (CIs) of geometric means for AUC and Cmax of roflumilast and roflumilast N-oxide and for oral apparent clearance (CL/F) of roflumilast were estimated.RESULTSDuring the steady-state of rifampicin, the AUC0–∞ of roflumilast decreased by 80% (point estimate 0.21; 90% CI 0.16, 0.27); Cmax by 68% (0.32; CI 0.26, 0.39); for roflumilast N-oxide, the AUC0–∞ decreased by 56% (0.44; CI 0.36, 0.55); Cmax increased by 30% (1.30; 1.15, 1.48); total PDE4 inhibitory activity decreased by 58% (0.42; 0.38, 0.48).CONCLUSIONSCo-administration of rifampicin and roflumilast led to a reduction in total PDE4 inhibitory activity of roflumilast by about 58%. The use of potent cytochrome P450 inducers may reduce the therapeutic effect of roflumilast. |
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Keywords: | CYP3A induction drug–drug interaction PDE4 inhibitor pharmacokinetics rifampicin roflumilast |
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