Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide.
OBJECTIVE
To investigate the effects of steady-state dosing of fluvoxamine, an inhibitor of cytochrome P450 (CYP) 1A2 and CYP2C19, on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor and its pharmacodynamically active metabolite roflumilast N-oxide.


METHODS
In an open-label, non-randomised, one-sequence, two-period, two-treatment crossover study, 14 healthy subjects received a single oral dose of roflumilast 500 microg on study day 1. After a 6-day washout period, repeated doses of fluvoxamine 50 mg once daily were given from days 8 to 21. On day 15, roflumilast 500 microg and fluvoxamine 50 mg were taken concomitantly. Percentage ratios of test/reference (reference: roflumilast alone; test: roflumilast plus steady-state fluvoxamine) of geometric means and their 90% confidence intervals for area under the plasma concentration-time curve, maximum plasma concentration (roflumilast and roflumilast N-oxide) and plasma clearance of roflumilast were calculated.


RESULTS
Upon co-administration with steady-state fluvoxamine, the exposure to roflumilast as well as roflumilast N-oxide increased by a factor of 2.6 and 1.5, respectively. Roflumilast plasma clearance decreased by a factor of 2.6, from 9.06 L/h (reference) to 3.53 L/h (test). The combined effect of fluvoxamine co-administration on roflumilast and roflumilast N-oxide exposures resulted in a moderate (i.e. 59%) increase in total PDE4 inhibitory activity.


CONCLUSIONS
Co-administration of roflumilast and fluvoxamine affects the disposition of roflumilast and its active metabolite roflumilast N-oxide most likely via a potent dual pathway inhibition of CYP1A2 and CYP2C19 by fluvoxamine. The exposure increases observed for roflumilast N-oxide are suggested to be attributable to CYP2C19 co-inhibition by fluvoxamine and thus, are not to be expected to occur when roflumilast is co-administered with more selective CYP1A2 inhibitors.
von Richter
Oliver
O
Exploratory Medicine, ALTANA Pharma AG, Konstanz, Germany.
Lahu
Gezim
G
Huennemeyer
Andreas
A
Herzog
Rolf
R
Zech
Karl
K
Hermann
Robert
R
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000328:Adult; D000631:Aminopyridines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D001549:Benzamides / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003521:Cyclopropanes / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D019388:Cytochrome P-450 CYP1A2; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D016666:Fluvoxamine / Q000008:administration & dosage / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D013607:Tablets; D013997:Time Factors
D000631:Aminopyridines; D014151:Anti-Anxiety Agents; D001549:Benzamides; D003521:Cyclopropanes; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D010726:Phosphodiesterase Inhibitors; D013607:Tablets; C424423:Roflumilast; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517734:roflumilast N-oxide; D016666:Fluvoxamine