Pharmacokinetics and pharmacodynamics of safinamide, a neuroprotectant with antiparkinsonian and anticonvulsant activity.
OBJECTIVE
This paper describes the pharmacokinetics and the pharmacodynamics, in terms of monoamino oxidase type B (MAO-B) inhibition, in male healthy volunteers of orally administered safinamide, a new neuroprotectant that in experimental models has demonstrated strong anticonvulsant and antiparkinson activities.


METHODS
Four clinical trials covering the dose range of 25-10,000 microg/kg were carried out to describe pharmacokinetics, pharmacodynamics and tolerability of safinamide, administered in single or repeated dose regimen to steady state, including a food interaction trial. All the above trials were carried out after the Ethics Committee's approval and signature of the consent form by the volunteers. In single dose trials blood sampling covered a 24 h-period in pharmacodynamic trials, 48 h-period in pharmacokinetic trials. In the case of repeated dose regimen to steady state a pre-dose sample was drawn on the first six study days, whereas the curve was explored on the 7th study day, prolonging blood sampling over a 48 h-period after the last dosing. Safinamide level was determined in plasma by a very sensitive and specific LC-MS-MS method, with a low limit of quantification of 0.5 ng/ml of plasma. Pharmacokinetic analysis was carried out with non-compartmental method and, in one case, also with the two-compartmental method. Monoamine oxidase activity of both types A and B (MAO-A and MAO-B) was determined in plasma at different times (MAO-B) and correlated to safinamide levels, or in urine (MAO-A).


RESULTS
Pharmacokinetics of safinamide proved to be linearly and proportionally related to the administered doses. The absorption of safinamide was rapid with peak plasma concentrations ranging from 2 to 4 h. Food prolonged the rate and did not affect the extent of absorption of safinamide. In repeat dose regimen once daily, the steady state was reached on the 5th study day with a marginal accumulation factor of 1.5-1.7. The drug was cleared with a t(1/2) of about 22 h. Safinamide reversibly inhibited MAO-B enzyme. Full inhibition was observed with single doses >/= 600 microg/kg, and a relevant, dose dependent, progressive inhibition was encountered with doses starting from 25 microg/kg. Even at the highest single dose of 10 mg/kg no evidence of MAO-A inhibition was observed.


CONCLUSIONS
Enteral absorption of the drug is linear and proportional to the doses administered. The drug is cleared from the body with a t(1/2) of approximately equal to 22 h, without producing any clinically relevant accumulation at steady state. The MAO-B inhibitory activity, without affecting MAO-A, is useful to prevent a dopamine bioinactivation in patients suffering from Parkinson's disease. Safinamide tolerability in the four clinical trials proved to be good.
Marzo
Antonio
A
IPAS SA, Via Mastri 36, 6853 Ligornetto (TI), Switzerland. antonio.marzo@ipas-research.com
Dal Bo
Lorenzo
L
Monti
Nunzia Ceppi
NC
Crivelli
Fabrizio
F
Ismaili
Shevqet
S
Caccia
Carla
C
Cattaneo
Carlo
C
Fariello
Ruggero G
RG
D000293:Adolescent; D000328:Adult; D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001596:Benzylamines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004032:Diet; D004041:Dietary Fats / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000097:blood; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D015203:Reproducibility of Results; D013686:Telemetry
D000927:Anticonvulsants; D000978:Antiparkinson Agents; D001596:Benzylamines; D004041:Dietary Fats; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D003577:Cytochrome P-450 Enzyme System; C092797:safinamide; D008995:Monoamine Oxidase; D000409:Alanine