Pharmacodynamics and Pharmacokinetics of Two Dose Regimens of Befloxatone, a New Reversible and Selective Monoamine Oxidase Inhibitor, at Steady State in Healthy Volunteers

The pharmacodynamic equipotency of 2 dose regimens (5 mg twice daily versus 10 mg once daily) of befloxatone, a new reversible and selective monoamine oxidase A (MAO‐A) inhibitor, after single and multiple doses for 6 days was examined in a randomized, double‐blind, three‐way crossover, placebo‐controlled trial of 12 healthy volunteers. Plasma levels of the deaminated metabolite 3–4 dihydroxyphenylglycol (DHPG), as measured by high‐performance liquid chromatography (HPLC) with coulometric electrochemical detection, were used as an index of MAO inhibition. A single dose of befloxatone produced a significant dose‐related reduction in plasma DHPG levels, as shown by the decrease in the 24‐hour area under the concentration‐time curve (AUC0–24) of DHPG, which peaked 2 hours after administration and persisted over 24 hours. Both dose regimens provided equipotent extent and duration of MAO‐A inhibition at steady state, suggesting a once daily dosage should be sufficient for most patients. The pharmacokinetic bioavailability at steady state of both dose regimens was also similar. The concentration‐time effect curve after a single dose revealed a hysteresis corresponding to the delay necessary to elicit MAO inhibition and/or elimination of DHPG. The relationship between plasma levels of DHPG and/or elimination of plasma concentrations of DHPG and befloxatone after a single dose can be modeled using the Emax model with a mean EC50 of 4.75 ng/mL, and suggests the presence of a maximal response from the single dose. This model permits prediction of steady‐state levels of DHPG.