PHARMACODYNAMICS AND PHARMACOKINETICS OF 2 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 v ersus 10 mg once daily) of befloxatone, a new reversible and selective monoamine oxidase A (MAO-A) inhibitor, after single and multiple dose s for 6 days was examined in a randomized, double-blind, three-way cro ssover, placebo-controlled trial of 12 healthy volunteers. Plasma leve ls of the deaminated metabolite 3-4 dihydroxyphenylglycol (DHPG), as m easured by high-performance liquid chromatography (HPLC) with coulomet ric electrochemical detection, were used as an index of MAO inhibition . A single dose of befloxatone produced a significant dose-related red uction in plasma DHPG levels, as shown by the decrease in the 24-hour area under the concentration-time curve (AUC(0-24)) of DHPG, which pea ked 2 hours after administration and persisted over 24 hours. Both dos e 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 close regimens was also similar. The concentration-time effec t 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 p lasma concentrations of DHPG and befloxatone after a single dose can b e modeled using the E(max) model with a mean EC(50) of 4.75 ng/mL, and suggests the presence of a maximal response from the single dose. Thi s model permits prediction of steady-state levels of DHPG.