Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects.
OBJECTIVE
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 microg 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 C(max) 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 AUC(0-infinity) of roflumilast decreased by 80% (point estimate 0.21; 90% CI 0.16, 0.27); C(max) by 68% (0.32; CI 0.26, 0.39); for roflumilast N-oxide, the AUC(0-infinity) decreased by 56% (0.44; CI 0.36, 0.55); C(max) 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.
Nassr
Nassr
N
Nycomed GmbH, 78467 Konstanz, Germany.
Huennemeyer
Andreas
A
Herzog
Rolf
R
von Richter
Oliver
O
Hermann
Robert
R
Koch
Manuela
M
Duffy
Kevin
K
Zech
Karl
K
Lahu
Gezim
G
D000328:Adult; D000631:Aminopyridines / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001549:Benzamides / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003521:Cyclopropanes / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; C424423:Roflumilast; D003577:Cytochrome P-450 Enzyme System; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517734:roflumilast N-oxide; D012293:Rifampin