Pharmacokinetic/pharmacodynamic relationships for otamixaban, a direct factor Xa inhibitor, in healthy subjects

Direct pharmocokinetic/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 pharmocokinetic/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 EC50 186 seconds (64%) for E-max, and 17seconds (16%) for E, 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 pharmocokinetics, allowed the anticoagulant effect at given doses of otamixaban to be foreseen in healthy subjects.