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Objective. The objectives of this study were to assess the effect of mirtazapine on steady-state pharmacokinetics of phenytoin and vice versa and to assess tolerability and safety of the combined use of mirtazapine and phenytoin.
Methods. This was an open-label, randomised, parallel-groups, single-centre, multiple-dose pharmacokinetic study. Seventeen healthy, male subjects completed either treatment A [nine subjects: daily 200 mg phenytoin for 17 days plus mirtazapine (15 mg for 2 days continuing with 30 mg for 5 days) from day 11 to day 17] or treatment B [eight subjects: mirtazapine, daily 15 mg for 2 days continuing with 30 mg for 15 days plus phenytoin 200 mg from day 8 to day 17]. Serial blood samples were taken for kinetic profiling on the 10th and 17th days of treatment A and on the 7th and 17th days of treatment B. Induction of CYP 3A by phenytoin was evaluated by measuring the ratio of 6β-hydroxycortisol over cortisol on the 1st, 7th and 17th days of treatment B.
Results. Co-administration of mirtazapine had no effect on the steady-state pharmacokinetics of phenytoin, i.e. the area under the plasma concentration–time curve (AUC)0–24 and peak plasma concentration (Cmax) remained unchanged. The addition of phenytoin to an existing daily administration of mirtazapine resulted in a mean (±SD) decrease of the AUC0–24 from 576±104 ng h/ml to 305±81.6 ng h/ml and a mean decrease of Cmax from 69.7±17.5 ng/ml to 46.9±10.9 ng/ml. Induction of CYP 3A by phenytoin is confirmed by the significantly (P=0.001) increased 6β-hydroxycortisol/cortisol ratio from 1.74±1.00 to 2.74±1.64.
Conclusion. Co-administration of mirtazapine did not alter the steady-state pharmacokinetics of phenytoin. The addition of phenytoin to an existing daily administration of mirtazapine results in a decrease of the plasma concentrations of mirtazapine by 46% on average, most likely due to induction of CYP 3A3/4.
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Spaans, .E., van den Heuvel, .M., Schnabel, .P. et al. Concomitant use of mirtazapine and phenytoin: a drug–drug interaction study in healthy male subjects. Eur J Clin Pharmacol 58, 423–429 (2002). https://doi.org/10.1007/s00228-002-0498-6
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DOI: https://doi.org/10.1007/s00228-002-0498-6