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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.
AuthorsLiguo Chi, Yun-Wen Pen, Ronald Potoczak, Glenn Gibson, Gary Hicks, Thomas E Mertz, Nancy Janiczek, Paul L Juneau, Kim Gallagher, Robert Leadley
JournalPharmacology (Pharmacology) Vol. 64 Issue 2 Pg. 76-83 (Feb 2002) ISSN: 0031-7012 [Print] Switzerland
PMID11803247 (Publication Type: Journal Article)
CopyrightCopyright 2002 S. Karger AG, Basel
Chemical References
  • Amidines
  • Anticoagulants
  • Biomarkers
  • Factor Xa Inhibitors
  • Pyridines
  • Fidexaban
Topics
  • Amidines (blood, pharmacology, therapeutic use)
  • Animals
  • Anticoagulants (blood, pharmacology, therapeutic use)
  • Biomarkers
  • Blood Coagulation (drug effects)
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Factor Xa Inhibitors
  • Humans
  • Partial Thromboplastin Time
  • Platelet Aggregation (drug effects)
  • Prothrombin Time
  • Pyridines (blood, pharmacology, therapeutic use)
  • Rabbits
  • Venous Thrombosis (drug therapy)

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