Hirudin elimination by hemofiltration: a comparative in vitro study of different membranes.
BACKGROUND
Recombinant hirudin (r-hirudin) is a highly specific and selective thrombin inhibitor. Since 1997, it has been approved for the treatment of heparin-induced thrombocytopenia (HIT type II). Renal function impairment drastically prolongs the elimination half-life time. In cases of bleeding or overdosage, there is currently no antidote available. Hemofiltration has been reported to be useful in r-hirudin elimination. In this study, we determined sieving coefficients (SCs) and drug clearances for two different hemofilters currently used in clinical medicine and intensive care.


METHODS
We developed an in vitro postdilution hemofiltration model using 500 ml heparinized (2 IU unfractionated heparin/ml) fresh human blood and bicarbonate substitution fluid. The investigated membranes were high-flux polysulfone F50 (1.0 m2, Fresenius) and AN69 Nephral 200 (1.05 m2, Hospal Cobe). After equilibration, a bolus of Lepirudin was injected into the postfilter port to achieve a r-hirudin blood level of approximately 15 microg/ml. Serial blood and ultrafiltrate samples were taken for the determination of hirudin levels (chromogenic assay) and control parameters. SC and clearances were calculated according to standard formulae.


RESULTS
The observed SCs and clearances differed significantly between F50 and Nephral 200 (0.60+/-0.17 and 21.0+/-5.9 ml/min, respectively, vs. 0.44+/-0.09 and 15.5+/-3.0 ml/min, respectively; P = 0.001). The determination of prothrombin fragments showed no coagulation activation during the experiments. The hematocrit values remained stable.


CONCLUSIONS
Our data show that r-hirudin can be eliminated by hemofiltration. The elimination obviously depends on the membrane material with high-flux polysulfone being more effective than AN69. These findings may be important in cases of overdosage and for r-hirudin dosage guidelines in continuous hemofiltration.
Frank
R D
RD
Medizinische Klinik II, Universitätsklinikum, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany. dario.frank@post.klinikum.rwth-aachen.de
Farber
H
H
Stefanidis
I
I
Lanzmich
R
R
Kierdorf
H P
HP
D000293:Adolescent; D000328:Adult; D006440:Hemofiltration / Q000379:methods*; D006493:Heparin / Q000097:blood / Q000494:pharmacology; D006629:Hirudins / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008658:Inactivation, Metabolic; D008567:Membranes, Artificial; D008875:Middle Aged; D011516:Prothrombin / Q000032:analysis; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics
D006629:Hirudins; D008567:Membranes, Artificial; D011994:Recombinant Proteins; D011516:Prothrombin; D006493:Heparin