Pharmacodynamic Analysis of the Anticoagulant Effects of Idraparinuxparinux after Termination of 6 and 12 Months Therapy for Prevention of Recurrent Venous Thromboembolism: Observations after the vanGogh Trials.

Idraparinux is a synthetic, polymethylated O-methyl, O-sulphate pentasaccharide with a higher affinity to antithrombin and has been investigated in patients with acute venous thromboembolism (VTE) for prophylaxis of recurrent events (vanGogh studies). 2.5 mg Idraparinux was given once weekly subcutaneously in patients with a creatinine clearance > 30 ml/min and continoued with 1.5 mg Idraparinux from the second injection in patients with lower creatinine clearance. This treatemnt was randomly compared to bodyweight adjusted enoxaparin followed by INR-adjusted warfarin for 3 to 6 months to prevent symptomatic recurrent VTE. The vanGogh extension trial randomised patients of the vanGogh trials or other patients with a 3 to 6 months course of warfarin after an initial first event of VTE for an additional double blind 6 months therapy of Idraparinux compared to placebo. The pharmacodynamic parameters of factor Xa (aXa) inhibition using the S2222 chromogenic substrate and Heptest assay were determined from plasma samples of 23 patients obtained after termination of a 6 or 12 months (Idraparinux for 6 months each in the DVT/PE and extension studies) therapy up to 15 months. The elimination half life of Idraparinux was 60±14 days (d, mean+SD) after termination of therapy (S2222) and 107±34 d (Heptest, p<0.0001) and did not differ between 6 and 12 months of treatment. The mean residence time differed between S2222 (75±31 d) and Heptest (121±49 d, p<0.0001) and not between 6 and 12 months. The Cmax was lower after 6 months of therapy compared to 12 months (S2222: 0.26±0.10 vs 0.44±0.08 μg/ml, p=0.0013, Heptest: 0.35±0.13 vs 0.54±0.11 μg/ml, p=0.0085). The volume of distribution was higher after 6 months of therapy compared to12 months (S2222: 8.5±3.5 vs 4.1±0.6 liter, p=0.0052, Heptest: 9.8±4.5 vs 4.7±1.3 liter, p=0.0145) without differences between the assays. The clearance differed between assays (S2222: 0.09±0.06. Heptest: 0.06±0.03 ml/min, p<0.0001) and was higher after 6 than after 12 months of treatment (S2222; 0.11±0.06 vs 0.05±0.02 ml/min, p=0.0088, Heptest: 0.07±0.03 vs 0.03±0.01 ml/min, p=0,0145). The data show a very long pharmacodynamic elimination half-life of 60 days or longer after termination of therapy after once weekly injection of Idraparinux. The half live is longer when determined by Heptest indicating also non-anti-factor Xa activities of Idraparinux. The steady state of Idraparinuxparinux is reached between 6 and 12 months of therapy or later. The low VTE-recurrence rate of 0.9% of patients randomized to placebo in the vanGogh Extension trial and after an initial course of 6 months of Idraparinux in the DVT/PE trial can be explained by the long half life of Idraparinux.