931-115 Phase I Studies on Inogatran, a New Selective Thrombin Inhibitor

Abstract

Inogatran is a new, synthetic, active site inhibitor of thrombin with a molecular weight of 439 dalton. Inogatran (pINN) selectively, rapidly and competitively binds thrombin with a Ki value of 15 nmol/l. In vitro it doubles the plasma thrombin time at a concentration of 23 nmol/1 and the activated partial thromboplastin time (APTT) at 1.1 μmol/1. Thrombin induced platelet aggregation is inhibited at an IC50 of 17 nmol/1 Inogatran was studied in healthy male human volunteers with regard to tolerability, pharmacokinetics and effects on haemostasis. It was given intravenously as a bolus in doses from 0.002 to 1.1 μmol/kg (n = 2-4 at each dose). The highest peak plasma concentration observed was 7 μmol/1 corresponding to an APTT prolongation of 3 times. The drug was also given as a constant infusion over 4 h at a dose of 0.73 μmol/kg per h (n = 16) which resulted in a mean plasma concentration at steady state of 1.9 μmol/l and an APTT prolongation of 2.3 times. Finally, it was given as a bolus with radiolabeled compound in a total dose of 25 μmol (n = 16). The drug was well tolerated and without side effects with the exception of slightly increased bleeding tendency at the blood sampling site. Inogatran had a volume of distribution of 0.26 ml/kg and a total plasma clearance of 6.1 ml/min per kg, resulting in a half life of about one hour. The drug was not metabolised and it was excreted unchanged with the elimination evenly distributed between urine and faeces. Ex vivo the thrombin time was linearly correlated to the plasma concentration while the APTT-concentration curve was non-linear. At the highest plasma concentrations a slight prolongation of the capillary bleeding time was seen in some subjects. Markers of thrombin activity (thrombin-antithrombin complex and prothrombin fragments 1–2) decreased during the constant infusion of the drug. There was no effect on fibrinolysis (PAI-l and t-PA activities) or protein C. It is concluded that inogatran is a safe and effective anticoagulant with favourable pharmacokinetics for i.v. use