Premium
Pharmacokinetics of Defibrotide in Non‐Human Primates is Dose Dependent.
Author(s) -
Fareed Jawed,
Hoppensteadt Debra,
Neville Brian,
McGeehan Elizabeth,
Iacobelli Massimo,
Jeske Walter
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1118.11
Subject(s) - defibrotide , pharmacokinetics , pharmacodynamics , dose , pharmacology , clotting time , bolus (digestion) , medicine , chemistry , coagulation , transplantation , hematopoietic stem cell transplantation
Defibrotide (DF) is a mammalian tissue derived polyelectrolyte which has been used for the treatment of arterial and venous thrombosis and microangiopathic disorders. Until recently indirect methods have been used to measure the levels of DF. More recently a colorimetric method, based on chromogenic coupling, is developed to measure the absolute amount of this agent. To investigate the absolute intravenous pharmacokinetics (PK) of DF in non‐human primates, graded dosages of defibrotide (1.0–5.0 mg/kg) were administered to individual groups of monkeys (n=6). Whole blood and plasma based clotting times were measured for up to 12 hours after the intravenous bolus at these dosages. In addition, tissue factor pathway inhibitor (TFPI) antigen levels and absolute levels of defibrotide were also measured using the colorimetric assay. The half life of 1.0, 2.5 and 5.0 mg/kg IV bolus ranged from 30–120 minutes. The peak concentration was also dependent on the dosage and ranged from 30±4 ug/ml suggesting a linear PK. DF produced minimal effects on the clotting assays, however, a dose dependent increase in TFPI antigen levels and defibrotide levels using a colorimetric method were observed. Repeated administration of defibrotide every 12 hours resulted in a progressive increase in AUC 0–12 , suggesting partial accumulation. In addition, at higher dose, DF resulted in an increased anti‐Xa activity which was dose independent. These studies clearly suggest that the pharmacologic actions of DF involve both the direct (plasmatic) and indirect pharmacodynamic components.