Desirudin is a highly potent and selective inhibitor of free circulating and clot-bound thrombin. A mean peak aPTT prolongation of around 1.4 times baseline value is observed following a subcutaneous (SC) b.i.d. injection of 15mg desirudin. At therapeutic serum concentrations it has no effect on other enzymes of the haemostatic system such as factors IXa, Xa, kallikrein, plasmin, tPA, or activated protein C. In addition, it does not display any effect on other serine proteases, such as the digestive enzymes trypsin or chymotrypsin, or on complement activation by the classical or alternative pathways.
The anticoagulant properties of desirudin are demonstrated by its ability to prolong the clotting time of human or rat plasma whether induced directly (thrombin time) or via the intrinsic (aPTT) or extrinsic (PT) pathways. Desirudin has no profibrinolytic activity.
In two controlled double blind clinical trials, the overall rate of thromboembolic events in patients treated with desirudin 15mg s.c. b.i.d. (N=370) was half that in patients treated with a standard dose of unfractionated heparin (N=396) (p<0.0001); the rate of proximal deep venous thrombosis was only one fifth that observed with the heparin (p<0.0001). To date clinical data are available on hip surgery only.
Mean absorption time of subcutaneous (SC) desirudin is 4.1, 4.5 and 5.4 h for dose levels of 0.1, 0.3 and 0.5 mg/kg, respectively (overall mean = 4.6 h). Absorption is complete based on mean area under the curve (AUC) values.
Following administration of single SC doses of 0.1-0.75 mg/kg, plasma concentrations of desirudin increased rapidly to maximum levels (Cmax) between 1 and 3 h. Both Cmax and AUC values are dose proportional.
Desirudin is distributed in the extracellular space with a distribution volume at steady state of 0.251/kg independently of the dose.
The disappearance of desirudin from plasma is rapid in the first phase with approximately 90% of an intravenous (IV) bolus dose disappearing from the circulation within 2 hours of the injection. A slower terminal elimination phase follows with a dose-independent mean terminal elimination half-life of 2 to 3 h. The mean residence times are 1.7-2 h and 6-7 h after IV and SC administration, respectively.
The total urinary excretion of unchanged desirudin amounts to 40-50 % of the administered dose. Metabolites lacking one or two C-terminal amino acids constitute a minor proportion of the material recovered from urine (<7%). In vitro and in vivo animal data indicate that desirudin is for the most part eliminated and metabolised by the kidney. Hepatic elimination of desirudin or the thrombindesirudin complex does not appear to be significant.
Total clearance of desirudin has been found to be in the same range following either SC or IV administration (ca 1.95-2.20ml/min/kg) and was dose-independent. The total and renal clearances of desirudin are slightly reduced in elderly subjects compared to young volunteers. This decrease can be considered unlikely to be of clinical significance, thus requiring no dose reduction.
Reproductive toxicology studies in animals showed desirudin to be teratogenic with changes comprising spina bifida in rabbits and omphaloceles in rats. Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
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