Study Of Coagulation And Platelets Response In An Open Label Randomised Non Treatment And Active Controlled (Dalteparin, Ximelagatran And Du-176b) In 4 Groups Of Elderly Healthy Subjects

Abstract Background: Several oral direct FXa inhibitors are being developed for the prevention and treatment of venous thrombosis. Their efficacy-safety ratio must be compared to that of LMWHs and oral direct FIIa inhibitors. Both families of drugs induce an alteration of blood coagulation through different mechanisms and after their interruption a possible coagulation rebound has been hypothesized. Patients and Method: In an open-label, randomised, non-treatment and active-controlled (Dalteparin, Ximelagatran), multiple dose study, 4 groups of 10 fed, elderly (64 to 75 years), healthy subjects were included to assess the pharmacodynamics of the oral direct anti-Xa DU-176b with a panel of biomarkers of blood coagulation, platelet and endothelium activation. Dalteparin 5000 anti-FXa (AFXa) IU SQ once a day, Ximelagatran direct anti-FIIa (AFIIa) 24 mg orally twice a day, and DU-176b AFXa 60 mg orally twice a day were the doses given while the 4th group received no treatment. Blood samples were collected before dosing and 1.5, 4, 12, and 24 hours after dosing on day one then on day 4 predose 12, 24, 48, and 72 hours after last drug administration. Results: Ximelagatran and DU-176b induced a consistent reduction of Thrombin-anti-Thrombin complexes (TAT) which was more marked than with Dalteparin. All study medications had a similar but moderate effect in reducing F1+2. Some clear differences were identified in the response of Thrombin Generation Test (TGT), Prothrombin Time (PT), and activated Partial Thromboplastin Time (aPTT). PT was more prolonged than aPTT with DU-176b. It was only slightly modified with Ximelagatran. These results deserve interest since all the study medications were used at doses considered as efficacious in the prevention of post operative thrombosis. No significant modification of platelet and endothelium biomarkers, soluble P selectin and CD 40L were evident. Interestingly anti-FXa amidolytic activity at peak levels were about 10 times higher with DU-176b than with Dalteparin when a LMWH reference preparation was used. Higher activity was maintained even at the trough level. Plasma drug concentrations were in good correlation with blood test results. No significant adverse events were observed and all subjects received all doses of study medication as planned. Most of the liver enzymes elevation were reported on day 7 after Dalteparin administration. Overall, there was no evidence of hypercoagulation or rebound effect following cessation of these three agents. Conclusion: Both PT and TGT would be the most preferable biomarker to evaluate efficacy of direct FXa inhibitor. And, no rebound phenomenon by any kind of anticoagulant was observed after short term treatment. DU-176b Dalteparin Ximelagatran No Treatment PT Peak ratio
 Trough 4th day 1.5
 1.1 1.05
 1.0 1.1
 1.0 1.05
 1.0 Remark: TFPI Variation (increase) only with Dalteparin aPTT peak ratio 1.30 1.24 1.44 0.98 Trough at 4th day 1.07 1.05 1.10 0.98 D D-Dimer peak/Trough ↓45% ↓33% ↓40% ↓10% D F1–2 nmol/L >↓40% ↓30% ↓40% ↓5% AFXa IU/ml peak 3.96 0.31–0.40 0.01 0.01 Trough 1.46 0.02 0.02 0.02 TGT Peak D MAX
 Trough ↓65 %
 ↓50 % ↓33 %
 ↓2 % ↓6 %
 ↓6 % ↓0
 ↓3% TGT-Lag Time Peak
 Trough x 5
 x 2.8 x 1.5
 x 1 x 1.6
 x 1.3 x 1.04
 x 1