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Randomized Controlled Trial
. 2005 Nov;60(5):486-93.
doi: 10.1111/j.1365-2125.2005.02467.x.

Fluvoxamine impairs single-dose caffeine clearance without altering caffeine pharmacodynamics

Kerry E Culm-Merdek  1 , Lisa L von Moltke, Jerold S Harmatz, David J Greenblatt
Affiliations
Randomized Controlled Trial

Fluvoxamine impairs single-dose caffeine clearance without altering caffeine pharmacodynamics

Kerry E Culm-Merdek et al. Br J Clin Pharmacol. 2005 Nov.

Abstract

Background: Coadministration of fluvoxamine impairs the clearance of caffeine and prolongs its elimination half-life, which is attributable to inhibition of CYP1A2 by fluvoxamine. The clinical importance of this interaction is not established.

Aim: To evaluate the effects of fluvoxamine on the kinetics and dynamics of single doses of caffeine.

Methods: Seven healthy subjects received single 250 mg doses of caffeine (or matching placebo) together with fluvoxamine (four doses of 100 mg over 2 days) or with matching placebo in a double-blind, four-way crossover study. For 24 h after caffeine or placebo administration, plasma caffeine and fluvoxamine concentrations were determined. Psychomotor performance, sedation, and electroencephalographic (EEG) "beta" frequency activity were also assessed.

Results: Fluvoxamine significantly reduced apparent oral clearance of caffeine (105 vs. 9.1 mL min(-1), P < 0.01; mean difference: 95.7 mL min(-1), 95% CI: 54.9-135.6), and prolonged its elimination half-life (4.9 vs. 56 h, P < 0.01; mean difference: 51 h, 95% CI: 26-76). Caffeine produced CNS-stimulating effects compared with placebo. However, psychomotor performance, alertness, or EEG effects attributable to caffeine were not augmented by coadministration of fluvoxamine.

Conclusions: Fluvoxamine greatly impaired caffeine clearance, but without detectable changes in caffeine pharmacodynamics. However, this study does not rule out possible adverse effects due to extensive accumulation of caffeine with daily ingestion in fluvoxamine-treated individuals.

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Figures

Figure 1
Figure 1
Plasma caffeine concentrations after the administration of caffeine with placebo (Treatment B) or during coadministration with fluvoxamine (Treatment D); each point is the mean (±SEM) for all subjects (n = 7) at the time shown
Figure 2
Figure 2
Plasma paraxanthine concentrations after the administration of caffeine with placebo (Treatment B) or during coadministration with fluvoxamine (Treatment D); each point is the mean (±SEM) for all subjects (n = 7) at the time shown
Figure 3
Figure 3
Plasma fluvoxamine concentrations after the administration of fluvoxamine with placebo (Treatment C) or during coadministration with caffeine (Treatment D); each point is the mean (±SEM) for all subjects (n = 7) at the time shown
Figure 4
Figure 4
Simulated plasma concentrations of caffeine after coadministration with either fluvoxamine or placebo for 7 consecutive days. It is assumed that the dose of caffeine and fluvoxamine are the same for each 24-h interval. Actual mean data points from the pharmacokinetic study are shown
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