Biological relevance of anti-recombinant hirudin antibodies--results from in vitro and in vivo studies.
This article provides an overview of the clinically relevant characteristics of antibodies directed toward recombinant (r) hirudin, with emphasis on the different ways in which these antibodies may influence pharmacokinetics and pharmacodynamics of r-hirudin. A high incidence of anti-hirudin antibody (AHAb) formation, mainly of the immunoglobulin G (IgG) subclass, was reported in up to 74% of patients treated with r-hirudin for more than 5 days. Like other drug-induced antibodies, AHAb may be responsible for accumulation or neutralization of the drug. Current clinical data support this assumption with reports on reduced metabolism, enhanced activity, and accumulation and neutralization of r-hirudin in the presence of AHAb. By examining AHAb developed in patients, we were able to demonstrate that AHAbs are capable of neutralizing r-hirudin in vitro. In addition, the anticoagulant activity of r-hirudin administered to Sprague-Dawley rats was almost completely abolished when a monoclonal mouse AHAb with known r-hirudin neutralizing capacity in vitro was injected intravenously. Because r-hirudin is mainly eliminated via the kidneys, formation of r-hirudin-AHAb complexes may, due to their size, result in accumulation of r-hirudin. We investigated filtration of r-hirudin incubated with monoclonal mouse AHAb by using high-flux hemodialyzers in a suitable in vitro model. Whereas sieving coefficients (SC) were high in the absence of AHAb, they were minimal (SC < 0.05) in the presence of AHAb. These findings may also be important when AHAb-positive patients treated with r-hirudin undergo hemofiltration procedures, which have recently been described as a rescue measure in case of r-hirudin overdosage. In vivo, the influence of a non-neutralizing monoclonal mouse AHAb on r-hirudin pharmacokinetics was examined in rats. Pharmacokinetic data compared with those of a control group without AHAb administration revealed that r-hirudin elimination half-life was significantly prolonged (59 +/- 25 minutes versus 142 +/- 25 minutes). This was accompanied by a decrease of total plasma clearance of r-hirudin. The volume of distribution of r-hirudin was significantly decreased (275 +/- 112 mL/kg versus 35 +/- 3 mL/kg), indicating that r-hirudin bound by AHAb is mainly distributed to the intravascular compartment. Taken together, both the half-life prolongation and the decrease of the volume of distribution contribute to r-hirudin accumulation and may explain respective findings in patients. In summary, two different effects of AHAbs seem to be clinically relevant: decreasing anticoagulant activity of r-hirudin by neutralization and accumulation of r-hirudin by reducing renal clearance. Formation of AHAbs has not yet been correlated with enhanced major bleeding complications. However, close monitoring of coagulation parameters is recommended in AHAb-positive patients during r-hirudin treatment.
Liebe
Volker
V
Department of Cardiology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany.
Brückmann
Martina
M
Fischer
Karl-Georg
KG
Haase
Karl Konstantin
KK
Borggrefe
Martin
M
Huhle
Günter
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002986:Clinical Trials as Topic; D004797:Enzyme-Linked Immunosorbent Assay; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology; D024764:Hirudin Therapy; D006629:Hirudins / Q000494:pharmacology*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007668:Kidney / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D006629:Hirudins; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D006493:Heparin