INTRAMUSCULAR DERMATAN SULFATE MF701 IN PATIENTS WITH HIP FRACTURE - RELATIONSHIP BETWEEN PHARMACOKINETICS AND ANTITHROMBOTIC EFFICACY

Two groups of 23 and 84 patients with hip fracture received intramuscu larly 100 and 300 mg dermatan sulfate (MF701) b. i. d., respectively, for the prophylaxis of deep vein thrombosis. Median duration of treatm ent was 17 and 16 days, respectively. Four blood samples were collecte d from each patient while under treatment. Plasma levels of dermatan s ulfate were determined by a chromogenic substrate assay. A one-compart ment model for multiple doses was employed to estimate the pharmacokin etic parameters. Fitting was applied to mean plasma concentrations cal culated for each sampling time and weighted according to the number of samples available at each time. Thrombin clotting time was measured o n the same plasma samples. Antithrombotic efficacy was assessed by bil ateral venography. Plasma levels of dermatan sulfate increased gradual ly throughout the treatment, indicating a marked accumulation process. Time to reach steady-state was 14 or 9 days with 100 or 300 mg b. i. d., respectively. This was due to an apparent prolonged terminal half- life (68 or 43 h), which actually reflected slow absorption from the i njection sites. The clinical efficacy of MF701 in preventing DVT was f ound to be dependent on the plasma concentration of the drug and also, but less significantly, on the prolongation of thrombin clotting time . Dermatan sulfate plasma levels greater than 9 mu g/ml are advisable to optimize efficacy in hip fracture patients.