Desirudin: effect on blood coagulation tests in vitro and following a subcutaneous administration in healthy volunteers

Desirudin (Revasc®), a recombinant hirudin, is a highly specific direct thrombin inhibitor indicated for the prevention and treatment of thromboembolic disorders. To assess the efficacy and predict the haemorrhagic risk of direct thrombin inhibitors, the ecarin clotting time (ECT) has gained attention relative to the more commonly used activated partial thromboplastin time (aPTT). The objective was to link ex vivo and in vitro therapeutic plasma concentrations of desirudin to various coagulation tests, in particular ECT. Six healthy subjects were administered a therapeutic dose (15 mg) of desirudin subcutaneously (s.c.). Plasma was collected at specified time points for 24 h to assess the effect of desirudin on aPTT, ECT, thrombin time (TT) and prothrombin time (PT) and to determine its pharmacokinetic profile. For the in vitro evaluation, human plasma spiked with concentrations of desirudin up to 725 nm, was analysed for the above mentioned coagulation tests. A mean (± s.d.) peak desirudin concentration of 27.1 ± 5.2 nm was reached at 2.2 ± 0.5 h. Maximum fold increase vs baseline in aPTT and ECT was 1.79 ± 0.16 and 1.34 ± 0.08 at 2.5 ± 1.0 and 1.8 ± 0.5 h, respectively. TT was immeasurably prolonged (>33 fold increase) up to 8 h post dose, while PT was hardly affected (1.05 ± 0.01). Based on the ex vivo data (Figure 1a), aPTT was more responsive than ECT and both parameters displayed a linear correlation with desirudin within the observed concentration range. In vitro data (Figure 1b) confirm the ex vivo results over the clinical concentration range, but show that for ECT, linearity extends up to much higher concentrations, while for aPTT the curve is markedly less than linear, starting at concentrations only slightly higher than those observed in the ex vivo study. Figure 1 ▪ aPTT, n = 91; ○ ECT, n = 96. Both aPTT and ECT are linearly correlated with desirudin concentrations observed following a 15 mg s.c. dose in healthy volunteers. Although aPTT is more responsive than ECT, in vitro data suggest that at higher doses of desirudin, ECT would be a more reliable parameter to monitor desirudin plasma concentrations, as it remains linear over a much wider concentration range compared with aPTT.