Key result
Entacapone increased R-warfarin exposure by 18% and INR by 13% compared to placebo in healthy subjects, but had no effect on the pharmacologically more potent S-warfarin enantiomer.
Why the study?
Does entacapone alter the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects?
RCT (n=12)
Double-blind
Randomized
No
Does entacapone alter the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects?
Effect estimate: Ratio 118% (95% CI 111-126)
Absolute Event Rate: 8.3% vs 7.02%
Entacapone has a minor pharmacokinetic interaction with R-warfarin but does not affect the more potent S-warfarin, suggesting it can be safely co-administered without clinically relevant pharmacodynamic effects.
Supports safe co-administration of entacapone with warfarin without dose adjustment; confirms enantiomer-specific interaction in RCT data.
AIMS: To investigate the influence of a multiple-dose regimen with the catechol-O-methyltransferase inhibitor entacapone on the pharmacokinetics and pharmacodynamics of warfarin. METHODS: In a randomized, double-blind, two-way cross-over study, 12 healthy subjects (gender ratio 1 : 1) received treatment for 1 week with either entacapone 200 mg four times daily or placebo during individually optimized treatment with warfarin (INR 1.4-1.8). The effect of entacapone on the steady-state pharmacokinetics of both R- and S-warfarin was determined and, in addition, INR values were measured. The key pharmacokinetic variables were AUCss, Cmax and tmax. RESULTS: Entacapone increased the exposure to R-warfarin by 18% (90% CI: 111, 126%), and caused a 13% (6, 19%) increase in INR values. No effect was seen on the pharmacokinetics of the pharmacologically more potent S-enantiomer. Safety and tolerability variables did not show any difference between the treatment phases. CONCLUSIONS: In healthy subjects, entacapone displays a slight pharmacokinetic interaction with R-warfarin but, based on the lack of a clinically relevant pharmacodynamic interaction, it appears that it can also be used safely in Parkinson's disease patients who are receiving warfarin.
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Dingemanse et al. (2002) conducted an RCT in Healthy subjects (n=12). Entacapone vs. Placebo was evaluated on Steady-state area under the concentration-time curve (AUCss) for R-warfarin (Ratio 118%, 95% CI 111-126). Entacapone increased R-warfarin exposure by 18% and INR by 13% compared to placebo in healthy subjects, but had no effect on the pharmacologically more potent S-warfarin enantiomer.
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