ABSTRACT
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.
KEYWORDS
Recombinant hirudin - anti-r-hirudin antibodies - neutralization - pharmacokinetics
- hemofiltration
