title: 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.
authors.affiliation: Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843-4474, USA. dnelson@cvm.tamu.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Nelson
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Nelson
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Miller
authors.forename: Robert
authors.initials: R
authors.lastname: Dupe
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Chahwala
authors.forename: Anthony
authors.initials: A
authors.lastname: Kennedy
authors.forename: Chaman
authors.initials: C
authors.lastname: Chander
authors.forename: Theresa W
authors.initials: TW
authors.lastname: Fossum
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001897:Boronic Acids / Q000493:pharmacokinetics*; D002315:Cardiopulmonary Bypass; D004151:Dipeptides / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D008943:Mitral Valve / Q000601:surgery*
chemical_list: C532470:(1-(((1-(1-oxo-2-N-((phenylmethoxy)carbonyl)-3-phenylpropyl)pyrrolidin-2-yl)carbonyl)amino)-4-methoxybutyl)-1-boronic acid; D000925:Anticoagulants; D001897:Boronic Acids; D004151:Dipeptides