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.
Patat
A
A
Medical Development Department, Synthelabo Recherche, Bagneux, France.
le Coz
F
F
Dubruc
C
C
Gandon
J M
JM
Durrieu
G
G
Cimarosti
I
I
Jezequel
S
S
Curet
O
O
Zieleniuk
I
I
Allain
H
H
Rosenzweig
P
P
D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000097:blood; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010080:Oxazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
D008996:Monoamine Oxidase Inhibitors; D010080:Oxazoles; C090014:befloxatone; D008734:Methoxyhydroxyphenylglycol; C010117:3,4-dihydroxyphenylglycol