Pharmacokinetics and pharmacodynamics of single and multiple doses of the MAO-B inhibitor lazabemide in healthy subjects.
OBJECTIVE
The objectives of this study were to assess the tolerability, pharmacokinetics and pharmacodynamics of the reversible monoamine oxidase B (MAO-B) inhibitor, lazabemide, in healthy subjects.


METHODS
Single and multiple (1 week) twice daily oral doses (100-350 mg) of lazabemide were administered sequentially to five groups of six healthy male subjects in a placebo-controlled, double-blind design. Adverse events, vital signs, and clinical laboratory variables were recorded. Pharmacokinetic parameters of lazabemide were determined after single and multiple doses. Pharmacodynamics were assessed by determination of MAO-B activity in blood platelets and intravenous tyramine potentiation tests.


RESULTS
Lazabemide was well tolerated at all dose levels, causing no clinically relevant changes in vital signs or laboratory parameters. Headache was the most frequent adverse event at higher doses. Lazabemide was rapidly absorbed and eliminated by mixed linear and non-linear pathway. Only minor accumulation occurred upon multiple dosing and steady-state plasma concentrations were achieved on the third day. Lazabemide caused a rapid and reversible inhibition of MAO-B activity in platelets. The twice daily dosing regimen resulted in complete inhibition at all dose levels. The duration of complete inhibition was dose-dependent and ranged from 16 h with 100 mg to 36 h with 350 mg. The sensitivity to i.v. tyramine did not change to a clinically relevant extent following single and multiple doses of lazabemide.


CONCLUSIONS
The clinical pharmacology characteristics of lazabemide did not differ markedly after single and multiple oral doses. A dose regimen of lazebemide 100 mg twice daily is anticipated because it caused full and continuous MAO-B inhibition.
Dingemanse
J
J
Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Wood
N
N
Jorga
K
K
Kettler
R
R
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010848:Picolinic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics*
D008996:Monoamine Oxidase Inhibitors; D010848:Picolinic Acids; C059303:lazabemide