Effect of Fluvoxamine on the Pharmacokinetics of Roflumilast and Roflumilast N-Oxide

Authors: Oliver von Richter,¹; Lahu, Gezim²; Huennemeyer, Andreas²; Herzog, Rolf³; Zech, Karl⁴; Hermann, Robert¹

Source: Clinical Pharmacokinetics, Volume 46, Number 7, 2007 , pp. 613-622(10)

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Abstract:

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 500μg on study day 1. After a 6-day washout period, repeated doses of fluvoxamine 50mg once daily were given from days 8 to 21. On day 15, roflumilast 500μg and fluvoxamine 50mg 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.

Conclusion: 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.

Keywords: Drug interactions; Fluvoxamine; Phosphodiesterase IV inhibitors; Roflumilast

Document Type: Research article

Affiliations: 1: 1 Exploratory Medicine, ALTANA Pharma AG, Konstanz, Germany 2: 2 Pharmacokinetics and Pharmacometrics, ALTANA Pharma AG, Konstanz, Germany 3: 3 Bioanalytics, ALTANA Pharma AG, Konstanz, Germany 4: 4 Preclinical Research, ALTANA Pharma AG, Konstanz, Germany

Publication date: 2007-01-01

Effect of Fluvoxamine on the Pharmacokinetics of Roflumilast and Roflumilast N-Oxide

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