CLINICAL-PHARMACOLOGY OF MOCLOBEMIDE DURING CHRONIC ADMINISTRATION OFHIGH-DOSES TO HEALTHY-SUBJECTS

The objectives of this study were to assess the tolerability, safety, pharmacodynamics and pharmacokinetics of high-dose moclobemide in heal thy subjects. Two sequential groups of six male and six female subject s (eight on active treatment, four on placebo) received for 8 days moc lobemide 450 mg b.i.d. and 600 mg b.i.d., respectively. Intravenous ty ramine presser tests were conducted at baseline, at the beginning of t reatment and at steady state. Oral tyramine presser tests with 50, 100 and 150 mg tyramine were conducted under steady-state conditions. Pha rmacokinetic parameters of moclobemide and two of its metabolites in p lasma and urine were determined after the first and last dose of moclo bemide The incidence and intensity of adverse events was dose-dependen t. The most frequently reported adverse events were insomnia, headache , dizziness and dry mouth. The IV tyramine presser sensitivity during both moclobemide dosing regimens was enhanced 3 to 4-fold. Intake of t yramine 50 mg did not result in systolic blood pressure increases grea ter than 30 mmHg. With regard to blood pressure increases, tyramine 10 0 mg is still compatible with moclobemide 450 mg b.i.d. but not with 6 00 mg b.i.d, The clearance of moclobemide decreased by about 60% on mu ltiple dosing, but no differences were found between both dosing regim ens. The urinary excretion of the N-oxide metabolite doubled during mu ltiple dosing. In conclusion, the maximum tolerated dose of moclobemid e in healthy subjects is 600 mg b.i.d. provided the tyramine content i n a meal is not higher than 50 mg.