Pharmacokinetic/pharmacodynamic relationships for otamixaban, a direct factor Xa inhibitor, in healthy subjects.
Direct pharmacokinetic/pharmacodynamic relationships for otamixaban were investigated after rising doses in healthy subjects using mixed-effect modeling. Activated partial thromboplastin time, prothrombin time, dilute prothrombin time, and Russell's viper venom-induced clotting time (RVVT) related linearly, whereas Heptest clotting time (HCT) followed a sigmoidal E(max) model. The pharmacokinetic/pharmacodynamic response (slope) and their corresponding interindividual variability (seconds per ng/mL, [% coefficient of variation]) were 0.263 (29%) for Russell's viper venom-induced clotting time, 0.117 (10%) for dilute prothrombin time, 0.058 (19%) for activated partial thromboplastin time, and 0.021 (11%) for prothrombin time. For Heptest clotting time, the parameter estimates with their corresponding interindividual variability (% coefficient of variation) were 71 ng/mL (30%) for EC(50), 186 seconds (64%) for E(max), and 17 seconds (16%) for E(0). The model predicted otamixaban plasma concentrations to double the clotting times that were close to those observed. These pharmacokinetic/pharmacodynamic relationships, together with the predictable pharmacokinetics, allowed the anticoagulant effect at given doses of otamixaban to be foreseen in healthy subjects.
Paccaly
Anne
A
Sanofi Aventis, 1041 Route 202-206, Mail Stop M303A, Bridgewater, NJ 08807-0800, USA. anne.paccaly@sanofi-aventis.com
Frick
Annke
A
Ozoux
Marie-Laure
ML
Chu
Valeria
V
Rosenburg
Ronald
R
Hinder
Markus
M
Shukla
Umesh
U
Jensen
Bradford K
BK
D000293:Adolescent; D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*
D003497:Cyclic N-Oxides; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011725:Pyridines; C435830:otamixaban