PHARMACODYNAMIC AND SAFETY RESULTS OF PEG-HIRUDIN IN HEALTHY-VOLUNTEERS

PEG-Hirudin, a chemically defined conjugate of recombinant hirudin and two molecules of polyethylene glycol (PEG)-5000 is a highly selective direct thrombin inhibitor with a significantly longer duration of act ion than non-conjugated recombinant hirudin permitting once daily subc utaneous administration. A series of placebo-controlled, randomized, P hase I clinical trials were conducted in 75 healthy volunteers to inve stigate the anticoagulant effects, safety and pharmacodynamics of PEG- Hirudin when administered intravenously as a bolus injection, infusion , and subcutaneously. After single i.v. injections of various doses of PEG-Hirudin (0.03-0.3 mg/kg) dose-dependent increases in anti-IIa act ivity and APTT were observed. Four hours after injection of 0.3 mg/kg, mean plasma concentration expressed in terms of anti-IIa activity was still 0.89 mu g/ml, corresponding to a 1.8-fold prolongation of APTT. Continuous intravenous infusions of 0.01 and 0.02 mg/kg/h PEG-Hirudin resulted in maximum anti-IIa activities of 0.42 mu g/ml and 0.77 mu g /ml, respectively, at the end of a six-hour infusion period without ha ving reached steady state at this time. After termination of the infus ion, anticoagulant activity displayed an immediate exponential decreas e. The anticoagulant activities of single subcutaneous doses of 0.05 t o 0.6 mg/kg were studied in a further series of investigations and slo w increases and prolonged durations of anti-IIa activity and APTT prol ongation were found. Repeated, once daily subcutaneous administrations of 0.2 to 0.4 mg/kg far five days resulted in dose-dependent prolonga tions of APTT and increases in anti-IIa activity without completely re aching steady state conditions. In a further study, 0.3 mg/kg of PEG-H irudin was given as an i.v., bolus injection followed by three repeate d single daily s.c. injections. In this trial, the APTT was shorter th an expected from previous studies; therefore, a direct comparison of v arious APTT reagents was made in the intravenous infusion trial. Of th e APTT reagents tested, BioMerieux Silimat and IL-ellagic acid proved to be the most sensitive to PEG-Hirudin. The hirudin derivative PEG-Hi rudin was. tolerated very well without immune-allergic side effects. I n view of the significantly prolonged anticoagulant efficacy in compar ison to non-conjugated r-hirudin, PEG-Hirudin is a promising compound especially for repeated once daily subcutaneous administration.