The specific thromboxane receptor antagonist S18886: pharmacokinetic and pharmacodynamic studies.
OBJECTIVE
We conducted a multicenter double-blind pharmacokinetic/pharmacodynamic (PK/PD) study of the new oral thromboxane receptor antagonist S18886 in 30 patients with peripheral artery disease, who were randomized to receive five different oral dosages of S18886 (1, 2.5, 5, 10 or 30 mg) for 12 weeks (83 days). Primary objective was to determine the effect of S18886 on platelet aggregation ex vivo.


RESULTS
Pharmacokinetics of S18886 was linear, with peak plasma levels being reached between 30 min and 2 h and a terminal half-life of 5.8-10 h. No significant accumulation of S18886 in plasma was observed after repeated dosing. The relationship between the S18886 concentration and platelet inhibition was examined in terms of U46619-induced platelet aggregation. Over the range of doses studied, there was a predictable relation between the plasma drug concentration and the degree of platelet inhibition at each dose. Maximal inhibition of U46619-induced platelet aggregation was achieved within 1 h with all oral doses of S18886, and this effect was maintained for at least 12 h. The PK/PD relationship was direct, and U46619-induced platelet aggregation was strongly inhibited by S18886 plasma concentrations above 10 ng mL(-1). This concentration was thus the minimal effective antiplatelet level in this population, and was maintained only by the dosages of 10 and 30 mg. The safety profile of S18886 was excellent, whatever the unit dose, with no attributable adverse events.


CONCLUSIONS
The results of this study, which included modeling and simulation, help identify the minimal effective plasma concentration of S18886 required for potent antiplatelet efficacy in patients with stable peripheral arterial disease.
Gaussem
P
P
Service d'Hématologie Biologique, Hôpital Européen Georges Pompidou (AP-HP), Paris, France. pascale.gaussem@egp.aphp.fr
Reny
J-L
JL
Thalamas
C
C
Chatelain
N
N
Kroumova
M
M
Jude
B
B
Boneu
B
B
Fiessinger
J-N
JN
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000378:metabolism; D000284:Administration, Oral; D000368:Aged; D016718:Arachidonic Acid / Q000378:metabolism; D019540:Area Under Curve; D003094:Collagen / Q000378:metabolism; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011422:Propionates / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013997:Time Factors
D009281:Naphthalenes; D010975:Platelet Aggregation Inhibitors; D011422:Propionates; D017482:Receptors, Thromboxane; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D003094:Collagen; C501362:terutroban