Pharmacodynamic and efficacy profile of TGN 255, a novel direct thrombin inhibitor, in canine cardiopulmonary bypass and simulated mitral valve repair

Abstract

Heparin-induced thrombocytopenia can be a life-threatening sequel to conventional use of unfractionated heparin in cardiopulmonary bypass (CPB). This study evaluated the pharmacokinetic/pharmacodynamic (PK/PD) and efficacy profile of a novel direct thrombin inhibitor, TGN 255, during cardiac surgery in dogs. Point-of-care coagulation monitoring was also compared against the plasma concentrations of TRI 50c, the active metabolite of TGN 255. The study was conducted in three phases using 10 animals: phase 1 was a dose-ranging study in conscious animals (n = 6), phase 2 was a similar but terminal dose-ranging study in dogs undergoing CPB (n = 6), and phase 3 was with animals undergoing simulated mitral valve repair (terminal) using optimal TGN 255 dose regimens derived from phases I and II (n = 4). During the study, PD markers and drug plasma levels were determined. In addition, determinations of hematologic markers and blood loss were undertaken. Phase 1 studies showed that a high-dose regimen of a 5-mg/kg bolus and infusion of 20 mg/kg/h elevated PD markers in conscious animals, at which time there were no measured effects on platelet or red blood cell counts, and the mean plasma concentration of TRI 50C was 20.6 microg/mL. In the phase 2 CPB dose-ranging study, this dosing regimen significantly elevated all the PD markers and produced hemorrhagic and paradoxical thrombogenic effects. In the phase 3 surgical study, a lower TGN 255 dose regimen of a 2.5-mg/kg bolus plus 10 mg/kg/h produced anticoagulation, elevated PD markers, and produced minimal post-operative blood loss in the animals. Plasma levels of TRI 50C trended well with the conventional point-of-care coagulation monitoring. TGN 255 provided effective anticoagulation in a canine CPB procedure, enabling successful completion with minimal blood loss. These findings support further evaluation of TGN 255 as an anticoagulant for CPB.

Figure 1.

Structure of TGN 255 (sodium salt).

Figure 2.

Plasma concentrations of TRI 50c in the conscious dose-range study using bolus plus infusion regimen for 90 minutes. Data values are expressed as mean (μg/mL) ± SEM.

Figure 3.

Changes in pharmacodynamic markers for TGN 255 in the CPB study using a 2.5-mg/kg bolus and 10-mg/kg/h infusion with reducing dose. Infusions were maintained for 90 minutes. Data values are expressed as clotting times (s) ± SD (n = 6).

Figure 4.

Paradoxical clotting associated with functional overdose of TGN 255.

Figure 5.

Changes in pharmacodynamic markers for TGN 255 using a 5-mg/kg bolus and 20-mg/kg/h infusion in the conscious dose-range study. Data values are expressed as mean (s) ± SD.

Figure 6.

Changes in platelet counts for TGN 255 in the CPB study using a 2.5-mg/kg bolus and 10-mg/kg/h infusion with reducing dose. Infusions were maintained for 90 minutes. Data values are expressed as mean counts (×1000) ± SD.

Figure 7.

Side by side comparisons of a 10-kg clinical case with similar ischemic and bypass times using heparin in a conventional fashion with a test subject using a 2.5-mg/kg bolus followed by a 10-mg/kg/h infusion of TGN 255. The heparin case is on the left.