Concomitant use of mirtazapine and phenytoin: a drug-drug interaction study in healthy male subjects.

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 6 beta-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 (C(max)) remained unchanged. The addition of phenytoin to an existing daily administration of mirtazapine resulted in a mean (+/-SD) decrease of the AUC(0-24) from 576+/-104 ng h/ml to 305+/-81.6 ng h/ml and a mean decrease of C(max) 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 6beta-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.

Effects of lacidipine on peak oxygen consumption, neurohormones and invasive haemodynamics in patients with mild to moderate chronic heart failure.

OBJECTIVE: To evaluate the efficacy and safety of the second generation dihydropyridine calcium channel blocker lacidipine in patients with heart failure. DESIGN: Placebo controlled, parallel group, double blind study over 8 weeks. SETTING: General community hospital in Breda, The Netherlands. PATIENTS: A random sample was studied of 25 outpatients with symptoms of mild to moderate heart failure, despite treatment with diuretics, digoxin, and angiotensin converting enzyme inhibitors. Their mean age was 65 years, with mean left ventricular ejection fraction of 0.24 and a peak oxygen consumption of 14.4 ml/min/kg. Two patients dropped out on lacidipine, one patient on placebo. INTERVENTION: Treatment with lacidipine 4 mg once daily or placebo for eight weeks. MAIN OUTCOME MEASURE: Cardiopulmonary exercise testing, invasive haemodynamics, and plasma neurohormones. RESULTS: Treatment with lacidipine 4 mg once daily, as compared to placebo treatment, significantly improved peak oxygen consumption (P < 0.02), cardiac index (P < 0.01), and stroke volume (P < 0.03) paralleled by a decrease in systemic vascular resistance (P < 0.03) and arteriovenous oxygen content difference (P < 0.01). Plasma noradrenaline, plasma renin activity, and aldosterone values did not differ between lacidipine and placebo. CONCLUSIONS: This second generation dihydropyridine may be of value as an adjunct to standard treatment in congestive heart failure patients.