Clinical pharmacology of moclobemide during chronic administration of high doses to healthy subjects.
The objectives of this study were to assess the tolerability, safety, pharmacodynamics and pharmacokinetics of high-dose moclobemide in healthy subjects. Two sequential groups of six male and six female subjects (eight on active treatment, four on placebo) received for 8 days moclobemide 450 mg b.i.d. and 600 mg b.i.d., respectively. Intravenous tyramine pressor tests were conducted at baseline, at the beginning of treatment and at steady state. Oral tyramine pressor tests with 50, 100 and 150 mg tyramine were conducted under steady-state conditions. Pharmacokinetic parameters of moclobemide and two of its metabolites in plasma and urine were determined after the first and last dose of moclobemide. The incidence and intensity of adverse events was dose-dependent. The most frequently reported adverse events were insomnia, headache, dizziness and dry mouth. The i.v. tyramine pressor sensitivity during both moclobemide dosing regimens was enhanced 3 to 4-fold. Intake of tyramine 50 mg did not result in systolic blood pressure increases greater than 30 mmHg. With regard to blood pressure increases, tyramine 100 mg is still compatible with moclobemide 450 mg b.i.d. but not with 600 mg b.i.d. The clearance of moclobemide decreased by about 60% on multiple dosing, but no differences were found between both dosing regimens. The urinary excretion of the N-oxide metabolite doubled during multiple dosing. In conclusion, the maximum tolerated dose of moclobemide in healthy subjects is 600 mg b.i.d. provided the tyramine content in a meal is not higher than 50 mg.
Dingemanse
J
J
Department of Clinical Pharmacology, F. Hoffmann-La Roche, Basel, Switzerland.
Wood
N
N
Guentert
T
T
Oie
S
S
Ouwerkerk
M
M
Amrein
R
R
D000328:Adult; D001549:Benzamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D020912:Moclobemide; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D011446:Prospective Studies; D014439:Tyramine / Q000494:pharmacology
D001549:Benzamides; D008996:Monoamine Oxidase Inhibitors; D020912:Moclobemide; D014439:Tyramine