Pharmacokinetics and pharmacodynamics of danaparoid during continuous venovenous hemofiltration: a pilot study.
BACKGROUND
In patients with suspected heparin-induced thrombocytopenia (HIT) who need renal replacement therapy, a nonheparin anticoagulant has to be chosen to prevent thrombosis in the extracorporeal circuit. Danaparoid, a low-molecular-weight heparinoid consisting of heparan sulphate, dermatan sulphate, and chondroitin sulphate, is recommended for systemic anticoagulation in patients with HIT. However, there are few data on the use of danaparoid in patients with acute renal failure, especially in patients dependent on renal replacement therapy such as continuous venovenous hemofiltration (CVVH). In the present study, we analyzed the pharmacokinetics and pharmacodynamics of danaparoid during CVVH in patients with suspected HIT.


METHODS
Based on a mathematical model, a dosing scheme for danaparoid was designed, aiming at anti-Xa levels of 0.5 to 0.7 U/mL, with a maximum of 1.0 U/mL. This dosing scheme was prospectively tested in the first CVVH run of a cohort of five patients with suspected HIT. CVVH with a blood flow rate of 150 mL/minute and a substitution rate of 2,000 mL/hour was performed with a cellulose triacetate membrane. Danaparoid was administered as a continuous infusion of 100 anti-Xa-U/hour after a loading dose of 3,500 anti-Xa-U. Serial measurements of anti-Xa activity and prothrombin fragment F1+2 were performed at baseline, at t = 5, 15, and 30 minutes, and at t = 1, 2, 4, 8, 16, and 24 hours after the danaparoid loading dose.


RESULTS
The median anti-Xa activity reached a maximum of 1.02 (0.66 to 1.31) anti-Xa-U/mL after 15 minutes and gradually declined to 0.40 (0.15 to 0.58) anti-Xa-U/mL over the span of 24 hours. Target anti-Xa levels were reached from 2 to 12 hours after the loading dose. Median prothrombin fragment F1+2 gradually decreased from 432 (200 to 768) to 262 (248 to 317) pmol/L after 24 hours. No bleeding or thromboembolic events occurred throughout the described treatment period.


CONCLUSIONS
Danaparoid administered by a continuous infusion of 100 anti-Xa-U/hour after a loading dose of 3,500 anti-Xa-U elicited target anti-Xa levels from 2 to 12 hours after the loading dose, without bleeding or thromboembolic events during the described CVVH treatment in patients with suspected HIT.
de Pont
Anne-Cornélie J M
AC
Department of Intensive Care Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. a.c.depont@amc.uva.nl
Hofstra
Jorrit-Jan H
JJ
Pik
Derk R
DR
Meijers
Joost C M
JC
Schultz
Marcus J
MJ
D000368:Aged; D000925:Anticoagulants / Q000494:pharmacology*; D002809:Chondroitin Sulfates / Q000494:pharmacology*; D015331:Cohort Studies; D003871:Dermatan Sulfate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006440:Hemofiltration / Q000379:methods*; D006497:Heparan Sulfate / Q000494:pharmacology*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010865:Pilot Projects; D011446:Prospective Studies; D013921:Thrombocytopenia / Q000628:therapy; D016896:Treatment Outcome
D000925:Anticoagulants; D002809:Chondroitin Sulfates; D003871:Dermatan Sulfate; D006497:Heparan Sulfate; C035838:danaparoid