Summary

Recombinant hirudin (r-hirudin) is a potent direct thrombininhibitor with immunogenic properties. Anti-hirudin antibodies(aHAb) are detected in up to 74% of patients treated withr-hirudin for more than 5 days. aHAb may alter the pharmacokineticsand pharmacodynamics of r-hirudin.The effects of aHAb on the pharmacokinetics of r-hirudin wereinvestigated in rats receiving r-hirudin intravenously eitherwithout aHAb (controls), 15 min after intravenous administrationof non-specific antibodies or aHAb, and after pre-incubationwith aHAb. When both were compared to controls andpre-treatment with non-specific antibodies, aHAb significantlyaltered the pharmacokinetics of r-hirudin with similar effects inboth approaches: In the presence of aHAb, the volume of distributionin a steady state and total plasma clearance werediminished, while the half-life of elimination was prolonged.Both the maximum r-hirudin plasma concentration and the area under the curve were increased. In addition, r-hirudin filtrationby high-flux hemodialyzer membranes (polysulfone,AN69) wasinvestigated 1) in the absence of aHAb, 2) in the presence ofnon-specific mouse antibodies, and 3) in the presence of threemonoclonal aHAb. In the absence of aHAb, both hemodialyzersallowed for significant r-hirudin filtration. Non-specific mouseantibodies did not markedly affect r-hirudin filtration. Bycontrast, all three aHAb almost completely hindered r-hirudinfiltration. aHAb varied in their capacity to neutralize r-hirudin.In conclusion, aHAb markedly alter the pharmacokinetics ofr-hirudin leading to r-hirudin accumulation. In the presence ofaHAb, hemofiltration does not allow for rapid reduction ofr-hirudin concentration. aHAb are capable of modifying pharmacodynamicsof r-hirudin. Close monitoring of aHAb-positivepatients treated with r-hirudin is considered mandatory.