Anti-hirudin antibodies alter pharmacokinetics and pharmacodynamics of recombinant hirudin.
Recombinant hirudin (r-hirudin) is a potent direct thrombin inhibitor with immunogenic properties. Anti-hirudin antibodies (aHAb) are detected in up to 74% of patients treated with r-hirudin for more than 5 days. aHAb may alter the pharmacokinetics and pharmacodynamics of r-hirudin. The effects of aHAb on the pharmacokinetics of r-hirudin were investigated in rats receiving r-hirudin intravenously either without aHAb (controls), 15 min after intravenous administration of non-specific antibodies or aHAb, and after pre-incubation with aHAb. When both were compared to controls and pre-treatment with non-specific antibodies, aHAb significantly altered the pharmacokinetics of r-hirudin with similar effects in both approaches: In the presence of aHAb, the volume of distribution in a steady state and total plasma clearance were diminished, 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 filtration by high-flux hemodialyzer membranes (polysulfone, AN69) was investigated 1) in the absence of aHAb, 2) in the presence of non-specific mouse antibodies, and 3) in the presence of three monoclonal aHAb. In the absence of aHAb, both hemodialyzers allowed for significant r-hirudin filtration. Non-specific mouse antibodies did not markedly affect r-hirudin filtration. By contrast, all three aHAb almost completely hindered r-hirudin filtration. aHAb varied in their capacity to neutralize r-hirudin. In conclusion, aHAb markedly alter the pharmacokinetics of r-hirudin leading to r-hirudin accumulation. In the presence of aHAb, hemofiltration does not allow for rapid reduction of r-hirudin concentration. aHAb are capable of modifying pharmacodynamics of r-hirudin. Close monitoring of aHAb-positive patients treated with r-hirudin is considered mandatory.
Fischer
Karl-Georg
KG
University Hospital Freiburg, Department of Medicine, Division of Nephrology and General Medicine, Hugstetter Str. 55, D-79106 Freiburg, Germany. fischer@med1.ukl.uni-freiburg.de
Liebe
Volker
V
Hudek
Renata
R
Piazolo
Lukas
L
Haase
Karl Konstantin
KK
Borggrefe
Martin
M
Huhle
Günter
G
D000818:Animals; D019540:Area Under Curve; D005260:Female; D006207:Half-Life; D017583:Hemodiafiltration; D006629:Hirudins / Q000097:blood / Q000276:immunology* / Q000493:pharmacokinetics*; D007518:Isoantibodies / Q000008:administration & dosage / Q000494:pharmacology*; D008567:Membranes, Artificial; D051381:Rats; D011994:Recombinant Proteins
D006629:Hirudins; D007518:Isoantibodies; D008567:Membranes, Artificial; D011994:Recombinant Proteins