Article date: October 2009
By: Nassr Nassr, Andreas Huennemeyer, Rolf Herzog, Oliver Von Richter, Robert Hermann, Manuela Koch, Kevin Duffy, Karl Zech, Gezim Lahu, in Volume 68, Issue 4, pages 580-587
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
AIMS
To 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.
METHODS
Sixteen 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.
RESULTS
During 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).
CONCLUSIONS
Co‐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.
DOI: 10.1111/j.1365-2125.2009.03478.x
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