Lepirudin

Lepirudin ([Leu1, Thr2]-63-desulfohirudin) is a recombinant hirudin derived from yeast cells. The polypeptide composed of 65 amino acids has a molecular weight of 6979.5 Dalton. Natural hirudin is produced in trace amounts as a family of highly homologous iso-polypeptides by the leech Hirudo medicinalis.

Lepirudin is a highly specific direct inhibitor of thrombin. Its activity is measured in a chromogenic assay. One anti-thrombin unit (ATU) is the amount of hirudin that neutralises one unit of WHO preparation 89/588 of thrombin. The specific activity of lepirudin is approximately 16,000 ATU/mg.

Its mode of action is independent of antithrombin III. Platelet factor 4 does not inhibit lepirudin. One molecule of hirudin binds to one molecule of thrombin and thereby blocks the thrombogenic activity of thrombin.

As a result all thrombin dependent coagulation assays are affected, e.g. the aPTT values increase in a dose-dependent fashion.

The pharmacokinetic properties of lepirudin following intravenous administration are well described by a two-compartment model. Distribution is essentially confined to extra-cellular fluids and is characterised by an initial half-life of approximately 10 minutes. Elimination follows a first order process and is characterised by a terminal half-life of about 1.3 hours in young healthy volunteers.

Both, excretion and metabolism take place in the kidney, and about 45 % of the dose administered is detectable in the urine. About 35% of the dose is excreted as unchanged compound.

The systemic clearance of lepirudin decreases in proportion to the existing glomerular filtration rate. In female patients the systemic clearance is about 25% lower as compared to male patients.

In elderly patients the systemic clearance of lepirudin is about 25% lower as compared to younger patients. Age alone causes a 7% reduction in clearance from the age of 30 to 70 years. The majority of the difference in clearance between young and elderly patients is due to the differences in renal function. In patients with terminal renal insufficiency prolonged elimination half-lives of about 2 days were observed.

General toxicity

Single and repeat-dose toxicity studies in mice, rats and monkeys showed the adverse responses that could be expected from an exaggerated pharmacodynamic impact of lepirudin. In monkeys retinal haemorrhages occurred. Moreover, in rats slight to moderate sinushistiocytosis of the regional lymph nodes and decreased haemosiderin deposits in the spleen were observed. Antibodies against hirudin which appeared in several of the treated monkeys resulted in prolongation of the terminal half-life and an increase in systemic exposure to lepirudin.

Mutagenicity

Lepirudin was not mutagenic or clastogenic in standard assays for such effects.