title: Assessment of ex vivo pharmacodynamic markers during inhibition of thrombosis by CI-1031 (ZK-807834), a novel direct factor Xa inhibitor.
abstract: CI-1031 (ZK-807834) is a novel, synthetic factor Xa (FXa) inhibitor with a Ki of 0.11 nM against human FXa. In human plasma in vitro, CI-1031 doubled PT and aPTT at 0.23 and 0.49 microM, respectively. The in vivo antithrombotic effect of CI-1031 was evaluated in a veno-venous shunt model of thrombosis in anesthetized rabbits. After thrombus formation was verified in the first shunts, rabbits received either vehicle or CI-1031 intravenously (bolus injection of 60, 240, or 480 microg/kg followed by an infusion of 2, 8, or 16 microg/kg/min for 140 min, respectively). The second shunts were inserted after 20 min of infusion of CI-1031 or vehicle. CI-1031 dose-dependently prolonged time to occlusion (TTO) in the second shunts (35 +/- 21, 62 +/- 24, and 120 +/- 0 min for the three dose groups, respectively, vs. 10 +/- 1 min for vehicle). Thrombus mass (TM) was reduced in a dose-dependent manner by CI-1031 (42 +/- 7, 27 +/- 6, and 18 +/- 4 mg vs. 50 +/- 4 mg for vehicle). Maximal TM reduction was 70% with an IC(50) of 0.6 microg/ml. Among all the coagulation parameters tested, PT had the best correlation with plasma CI- 1031 concentration (r = 0.97). Ex vivo plasma anti-FXa activity was also well correlated with plasma concentration of CI-1031 and with PT (r = 0.96 and 0.98, respectively). These results indicate that CI-1031, which is currently undergoing clinical evaluation, is an effective antithrombotic compound with a favorable efficacy-to-bleeding ratio. In addition, CI-1031 concentration in plasma can be monitored using PT or anti-Xa assays, thereby providing reliable methods to ensure safe and accurate dose titration of CI-1031.
authors.affiliation: Cardiovascular Therapeutics, Pfizer Global R&D, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. Liguo.Chi@pfizer.com
authors.forename: Liguo
authors.initials: L
authors.lastname: Chi
authors.forename: Yun-Wen
authors.initials: YW
authors.lastname: Pen
authors.forename: Ronald
authors.initials: R
authors.lastname: Potoczak
authors.forename: Glenn
authors.initials: G
authors.lastname: Gibson
authors.forename: Gary
authors.initials: G
authors.lastname: Hicks
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Mertz
authors.forename: Nancy
authors.initials: N
authors.lastname: Janiczek
authors.forename: Paul L
authors.initials: PL
authors.lastname: Juneau
authors.forename: Kim
authors.initials: K
authors.lastname: Gallagher
authors.forename: Robert
authors.initials: R
authors.lastname: Leadley
mesh_terms: D000578:Amidines / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000925:Anticoagulants / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers; D001777:Blood Coagulation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D006801:Humans; D010314:Partial Thromboplastin Time; D010974:Platelet Aggregation / Q000187:drug effects; D011517:Prothrombin Time; D011725:Pyridines / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D020246:Venous Thrombosis / Q000188:drug therapy*
chemical_list: D000578:Amidines; D000925:Anticoagulants; D015415:Biomarkers; D065427:Factor Xa Inhibitors; D011725:Pyridines; C114592:Fidexaban