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Aims: 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.

1. Single oral doses (100-300 mg) and multiple oral doses (100-350 mg 12 hourly for 7 days) of lazabemide were administered to 35 young and 40 elderly healthy subjects. Plasma concentrations of unchanged drug were determined to study the dose-concentration relationship. 2. The elimination phase time course of lazabemide concentrations indicated concentration-dependent elimination after both single and multiple dosing. Nevertheless, maximum concentrations and areas under concentration-time curves increased almost proportionally with dose and accumulation after chronic dosing was less than a factor of 2; steady-state concentrations were achieved by the third day of dosing. The apparent half-life determining accumulation was approximately 8-9 h. 3. Drug absorption commenced rapidly after a dose; two components to the absorption process were detectable in young subjects possibly due to simultaneous administration of multiple tablets at the higher doses. 4. Observations after single and multiple dosing were described with a compartmental model allowing for parallel saturable (population mean +/- s.d.: maximum elimination rate Vmax/F: 2.8 +/- 1.4 mg h-1; concentration at half-maximum elimination Km: 36 +/- 19 micrograms l-1) and first-order (CL/F 16 +/- 3.8 l h-1) elimination pathways. No important difference between the young and the elderly subjects was noted in absorption or disposition parameters of lazabemide.