The antithrombotic effects of CI-1028, an orally bioavailable direct thrombin inhibitor, in a canine model of venous and arterial thrombosis.
Direct thrombin inhibitors represent a new class of drug that may offer a therapeutic alternative for the treatment and prevention of thrombembolic conditions, especially on the venous side of the systemic circulation. CI-1028 (PD 172524/LB30057) is a potent, highly selective inhibitor of thrombin that is orally bioavailable. The efficacy of this compound has been demonstrated in animal models in which intra-venous administration was used. The objective of this study was to evaluate the efficacy of CI-1028 after oral administration in a canine electrolytic injury model of venous and arterial thrombosis. CI-1028 was administered via oral gavage, and animals received either saline or 10, 15, 20, or 30 mg/kg of drug. Fifteen minutes later, the dogs were anesthetized and a femoral artery and vein were exposed and instrumented to induce electrolytic injury and thrombosis while continuously monitoring blood flow in the vessels. Maximum blood CI-1028 concentrations of 0.88+/-0.27, 1.8+/-0.3, 2.2+/-0.5, and 3.2+/-0.5 microg/mL were generally achieved 15 to 30 minutes after administering the compound in the 10-, 15-, 20-, and 30-mg/kg groups, respectively. Administration of CI-1028 increased the time to occlusion (TTO), the principal efficacy end point, in a dose-dependent manner in both arteries and veins. The TTO in the control group (n=8) averaged 66+/-11 minutes in the arteries and 69+/-6 minutes in the veins. In dogs treated with 10 mg/kg (n=8), the TTO was not significantly different from that of the control group. In the 15-mg/kg group (n=9) TTO averaged 140+/-27 minutes in the arteries (p=not significant) and 125+/-15 minutes (p<0.05) in the veins. In the 20-mg/kg group (n=8), TTO was significantly longer than controls in both types of vessels, averaging 168+/-30 minutes in the arteries (p=0.05) and 155+/-21 minutes (p<0.05) in the veins. Likewise, at 30 mg/kg (n=8) both the arterial (179+/-17 minutes) and venous (188+/-15 minutes) TTO was significantly prolonged compared with controls. Surgical blood loss and template bleeding times tended to increase in a dose-dependent manner but a statistically significant elevation was detected for template bleeding time only at the highest dose. Dramatic changes in thrombin time were detected, consistent with the CI-1028 mechanism of action. Virtually no changes were detected in prothrombin time. Maximum activated partial thromboplastin time (aPTT) and activated clotting time changes were detected approximately 30 minutes after dosing, and they were approximately twofold and fivefold baseline values, respectively, at the highest dose. In conclusion, these results demonstrate that CI-1028 provides dose-dependent antithrombotic efficacy after oral administration in a canine model of venous and arterial thrombosis.
McClanahan
T B
TB
Cardiovascular Therapeutics, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA. tom.mcclanahan@wl.com
Hicks
G W
GW
Ignasiak
D P
DP
Bousley
R
R
Mertz
T E
TE
Juneau
P
P
Janiczek-Dolphin
N
N
Kim
I C
IC
Gallagher
K P
KP
D000284:Administration, Oral; D000818:Animals; D001157:Arterial Occlusive Diseases; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D001780:Blood Coagulation Tests; D001783:Blood Flow Velocity / Q000187:drug effects; D016063:Blood Loss, Surgical; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology; D006470:Hemorrhage / Q000139:chemically induced; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy*; D020246:Venous Thrombosis
D001549:Benzamides; D005343:Fibrinolytic Agents; C116605:LB 30057; D013917:Thrombin