The mechanism of action of defibrotide sodium has not been fully elucidated. In vitro, defibrotide sodium enhances the enzymatic activity of plasmin to hydrolyze fibrin clots. Studies evaluating the pharmacological effects of defibrotide sodium on endothelial cells (ECs) were conducted primarily in the human microvascular endothelial cell line. In vitro, defibrotide sodium increased tissue plasminogen activator (t-PA) and thrombomodulin expression, and decreased von Willebrand factor (vWF) and plasminogen activator inhibitor‑1 (PAI-1) expression, thereby reducing EC activation and increasing EC‑mediated fibrinolysis. Defibrotide sodium protected ECs from damage caused by chemotherapy, tumor necrosis factor-α (TNF-α), serum starvation, and perfusion.
At a dose 2.4 times the maximum recommended dose, defibrotide does not prolong the QTc interval to any clinically relevant extent.
Plasma concentrations of PAI-1 were assessed on an exploratory basis as a potential pharmacodynamic marker for efficacy in Study 2. PAI-1 is an inhibitor of t-PA and therefore of fibrinolysis. Mean PAI-1 levels on Days 7 and 14 were lower than those at baseline in patients with complete response (CR) and in those who were alive at Day+100, but this trend did not reach statistical significance. There were no statistically significant differences in mean PAI-1 levels by treatment or outcome.
After intravenous administration, peak plasma concentrations of defibrotide sodium occur approximately at the end of each infusion.
Defibrotide sodium is highly bound to human plasma proteins (average 93%) and has a volume of distribution of 8.1 to 9.1 L.
Metabolism followed by urinary excretion is likely the main route of elimination. The estimated total clearance was 3.4 to 6.1 L/h. The elimination half-life of defibrotide sodium is less than 2 hours. Similar plasma concentration profiles were observed in VOD patients after initial and multiple-dose administration of 6.25 mg/kg every 6 hours for 5 days. Therefore, no accumulation is expected following multiple-dose administration.
Though the precise pathway of defibrotide sodium degradation in plasma in vivo is largely unknown, it has been suggested that nucleases, nucleotidases, nucleosidases, deaminases, and phosphorylases metabolize polynucleotides progressively to oligonucleotides, nucleotides, nucleosides, and then to the free 2'-deoxyribose sugar, purine and pyrimidine bases.
The biotransformation of defibrotide sodium was investigated in vitro by incubation with human hepatocytes from donors of different ages and showed that defibrotide sodium does not undergo appreciable metabolism by human hepatocyte cells.
After administration of 6.25 mg/kg to 15 mg/kg doses of defibrotide as 2-hour infusions, approximately 5-15% of the total dose was excreted in urine as defibrotide sodium, with the majority excreted during the first 4 hours.
Insufficient PK data were collected in pediatric patients to draw conclusions.
The safety, tolerability, and pharmacokinetics of 6.25 mg/kg as 2-hour intravenous infusions of defibrotide were evaluated in patients with Hemodialysis-dependent End Stage Renal Disease (ESRD) during hemodialysis and on days off dialysis, and in patients with severe renal disease or ESRD not requiring dialysis. Defibrotide sodium was not removed by hemodialysis, which had no notable effect on plasma clearance of defibrotide sodium. Terminal half-lives were consistently less than 2 hours, and there was no accumulation of defibrotide sodium following repeated dosing. Defibrotide sodium exposure (AUC) in patients with severe renal impairment or ESRD was 50% to 60% higher than that observed in matched healthy subjects. Peak concentration (Cmax) was 35% to 37% higher following single- and multiple-dose administration of defibrotide sodium.
Pharmacokinetic drug-drug interactions are unlikely at therapeutic dose. Data from in vitro studies using human biomaterial demonstrate that defibrotide sodium does not induce (CYP1A2, CYP2B6, CYP3A4, UGT1A1) or inhibit (CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C9, CYP2C19, CYP2D6, UGT1A1, UGT2B7) the major drug metabolizing enzymes and is not a substrate or inhibitor of the major drug uptake transporters (OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3) or efflux transporters (P-gp and BCRP).
There is some evidence (animal studies, ex vivo human plasma, and healthy volunteers) that defibrotide sodium may enhance the pharmacodynamic activity of heparin and alteplase.
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