Pressor Effect of Oral Tyramine During Treatment with Befloxatone, a New Reversible Monoamine Oxidase‐A Inhibitor, in Healthy Subjects

Abstract

The interaction between tyramine and befloxatone, a new selective, reversible monoamine oxidase-A (MAO-A) inhibitor, was studied in a single-blind, parallel-group study in 30 healthy male volunteers whose fasting tyramine 30 dose (Tyr30) was 400 or 600 mg. Each subject completed a placebo run-in period followed by a befloxatone period. Befloxatone was given in repeated doses according to one of three regimens: befloxatone 20 mg once daily at the end of a meal rich in tyramine or befloxatone 10 or 20 mg twice daily 2 hours before a meal rich in tyramine. Subjects were given increasing daily doses of tyramine mixed with the meal, until a systolic blood pressure increase of at least 30 mm Hg was achieved (Tyr30). The mean Tyr30 decreased from 1220 mg (range, 600-1800 mg) during placebo to 290 mg (range, 150-500 mg) during befloxatone 20 mg once daily, 250 mg (range, 100-300) during befloxatone 10 mg twice daily, and 155 mg (range, 100-250 mg) during befloxatone 20 mg twice daily; corresponding to a potentiation factor of 5.2-, 6.5-, and 7.9-fold, respectively. The extent and the duration of the systolic blood pressure increase did not significantly differ between the placebo and the befloxatone regimens, except for a longer duration with the 20-mg twice daily regimen. These results are similar to those reported with the therapeutic dosage of other selective MAO-A inhibitors. They suggest that there would be little risk of hypertensive crisis in patients treated in clinical studies with befloxatone, and thus dietary restrictions appear to be unnecessary when the drug is given in a regimen of up to 20-mg once daily after meals.

Monoamine Oxidase Inhibitors—Revisiting a Therapeutic Principle

“…Cimoxatone was never registered for the market as it caused a tyramine pressure response comparable to the irreversible inhibitor clorgyline (Emilien, 1999). Befloxatone (Consonar, MD370, 503), another MAO-A selective inhibitor of the same class with a high affinity for MAO-A (2 nM), was developed in the 1990s for the treatment of depression by Synthelabo (France) (Patat et al, 1995;Curet, 1996).…”

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

“…Indeed, it has been reported that increasing mainly lipid but also protein content of the meal significantly reduce the tyramine blood pressor response (Audebert et al, 1992). Bioavailability of tyramine when administered with food or as a dietary constituent seems to drastically be reduced and systematic concentrations are reduced by approximately 2-to 3-fold (Patat et al, 1995;Van den Berg et al, 2003;Azzaro et al, 2006).…”

“…The results from literature showed that from 600 mg up to 2,000 mg of tyramine administrated in a meal would be needed to cause a minimal systolic blood pressure increase (of at least 30 mmHg). Therefore the intestinal barriers to tyramine in non-medicated healthy volunteers (placebo groups) seem to be effective to avoid tyramine intoxication from food (Korn et al, 1988a;Berlin et al, 1989;Zimmer et al, 1990;Patat et al, 1995). A doseresponse curve was generated by Patat et al (1995), in which 1100 mg of tyramine correspond to the effective dose (ED 50 ) as the tyramine dose at which 50% of the individuals responded.…”

“…Therefore the intestinal barriers to tyramine in non-medicated healthy volunteers (placebo groups) seem to be effective to avoid tyramine intoxication from food (Korn et al, 1988a;Berlin et al, 1989;Zimmer et al, 1990;Patat et al, 1995). A doseresponse curve was generated by Patat et al (1995), in which 1100 mg of tyramine correspond to the effective dose (ED 50 ) as the tyramine dose at which 50% of the individuals responded. According to Bieck and Antonin (1988) intraindividual coefficient of variation was around 10% in repeated tests and there was no correlation with sex, age or weight.…”

“…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.…”