Comparative Pharmacodynamics of TGN 255, a Novel Direct Thrombin Inhibitor and Unfractionated Heparin in Healthy Volunteers.

Background: TGN255 is a synthetic direct thrombin inhibitor undergoing development for the prevention of arterial and venous thrombosis in high risk patients.

Methods: An open-label, heparin-controlled, cross-over study was performed in 12 healthy male volunteers to evaluate the pharmacokinetics, pharmacodynamics and safety of TGN255 and heparin given as an infusion over a 3 hour period. Doses of TGN255 were given as a bolus of 25 mg over 60 sec followed by a 3 h infusion of 40, 80, 160 mg/h. Heparin was administered as a 5000 IU bolus followed by 15 IU/kg/h infusion for 3 h. Plasma concentrations of TGN255 were evaluated using a validated LC-MS/MS method. The dynamic activity was assessed through measurement of the Activated Clotting Time (ACT), thrombin time (TT) and activated Partial Thromboplastin Time (aPTT).

Results: The plasma concentration of TGN255 rapidly increased following the bolus injection, and the pharmacokinetic profile of TGN255 was dose proportional. The effective half-life of TGN255 was 1.7 h. This short half-life was consistent with the rapid decline in the observed TT, aPTT and ACT ratios after administration was completed. The elevations in TT ratios were considerably higher than for the aPTT ratios across TGN255 groups (6.9, 11.7, 19.7 times baseline for TT and 1.7, 2, 2.4 times baseline for aPTT). The relationship between TT ratio and TGN255 plasma concentration was very well defined with a correlation coefficient of 0.94. For heparin, the TT ratios reflected a saturated system (measurements >300 s) and the aPTT ratios showed a marked increase compared to TGN255 groups (mean of 9.3 times baseline) indicating less selective behavior than TGN255 for this clotting parameter. The ratios for ACT showed a measurable elevation above baseline: mean of 1.9, 2.2, 2.7 for TGN255 groups versus 1.7 for heparin. No significant adverse events have been observed of either a general or cardiovascular nature (including hemorrhage, ECG changes, or liver function tests).

Conclusions: This study will support the entry of TGN255 into the clinical arena of cardiovascular procedures, and support its use in patients undergoing coronary artery bypass grafting.