Clinical pharmacology of moclobemide during chronic administration of high doses to healthy subjects

Abstract

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.

Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: A revision of the 2005 guidelines from the British Association for Psychopharmacology

“…Interactions involving traditional MAOIs and serotonergic antidepressants such as SSRIs and clomipramine can be hazardous (Lane and Baldwin, 1997). Moclobemide, a reversible inhibitor of mono-amine oxidase A (RIMA) has proven efficacy in social phobia [IV] (Blanco et al, 2013) and some evidence of benefit in panic disorder [I (PCT)] (Ross et al, 2010): the reversibility of its action reduces the need for dietary restrictions at lower daily doses though avoidance of tyramine-containing foods is advisable at higher dosage [I (PCT)] (Dingemanse et al, 1998).…”

Scientific Opinion on risk based control of biogenic amine formation in fermented foods

“…In these cases, the increase in tyramine sensitivity has been reported to range from 2-5-fold (selegiline), 5-7-fold (moclobemide) to 13-fold (phenelzine) depending on the MAOI dosage (Prasad el al., 1988;Bieck and Antonin, 1988;Bieck and Antonin, 1989;Berlin et al, 1989;Zimmer et al, 1990). According to the literature, 6 mg of tyramine could provoke mild crisis and 10 -25 mg severe headache with intracranial haemorrhage in patients treated with classical MAOI (McCabe, 1986), whereas from 50 up to 150 mg of tyramine would be well tolerated by patients under new generation MAOI treatment, so called RIMA (reversible inhibitors of MAO-A) (Korn et al, 1988b;Dingemanse et al, 1998;Patat et al, 1995). Tyramine has also been incriminated as a causative agent of certain food-induced migraines, together with phenylethylamine.…”

“…Other reports conclude that from 50 up to 150 mg of tyramine would be well tolerated by patients under new generation MAOI treatment, so called RIMA (reversible inhibitors of MAO-A) ( Table 4; Korn et al, 1988a,b;Dingemanse et al, 1998;Patat et al, 1995).…”

Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity

“…Peak concentration (C max ) increases linearly with dose (although there is substantial interindividual difference [22]), and almost doubles at steady state after 10 days of multiple doses [34].…”

“…Clearance is also reduced at steady state, suggesting that moclobemide may reduce its own metabolism [22]. However, the plasma concentration-time curves remain log-linear before and after multiple dose administration, indicating that there is inhibition of metabolism (possibly metabolite inhibition), rather than overall saturation of metabolism [22,34,36,39].…”