Defibrotide is an oligonucleotide mixture with demonstrated antithrombotic, fibrinolytic, anti-adhesive and anti-inflammatory actions. The mechanism of action is multifactorial. It primarily acts through reducing excessive endothelial cell (EC) activation (endothelial dysfunction), modulating endothelial homeostasis as well as restoring thrombo-fibrinolytic balance. However, the exact mechanism of action of defibrotide is not fully elucidated.
Defibrotide has demonstrated antithrombotic and fibrinolytic effects in vitro and in vivo by: increasing systemic tissue factor pathway inhibitor (TFPI), tissue plasminogen activator (t-PA) and thrombomodulin ™ expression; decreasing von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) expression; and enhancing the enzymatic activity of plasmin to hydrolyse fibrin clots.
In vitro and in vivo studies have demonstrated that defibrotide inhibits leukocyte and platelet adhesion to endothelium by: suppressing P-selectin and vascular cell adhesion molecule-1 (VCAM)-1; interfering with lymphocyte function-associated antigen 1-intercell adhesion molecule (LFA-1-ICAM) mediated leukocyte transmigration; and increasing nitric oxide (NO), Prostaglandin I2 (PGI2) and Prostaglandin E2 (PGE2).
In vitro defibrotide demonstrates anti-inflammatory effects that attenuate the release and production of reactive oxygen species and inflammatory mediators such as interleukin 6, thromboxane A2, leukotriene B4 and tumour necrosis factor-α (TNF-α).
Defibrotide protects ECs from damage and promotes tissue homeostasis by decreasing fludarabine-mediated apoptosis of EC while maintaining its anti-leukemic effect and by inhibiting the expression of heparanase, shown in in vitro and in vivo studies respectively.
In 52 healthy volunteers, after a single 6.25 mg/kg dose of defibrotide given as a 2-hour infusion, the pharmacokinetic parameters were as follows:
Defibrotide pharmacokinetic parameters after intravenous infusion of 6.25 mg/kg to healthy subjects:
| Parameter | Defibrotide PK Parameters Mean ± SD |
|---|---|
| Cmax (μg/mL) | 17.3 ± 3.83 |
| tmax (h)# | 2.00 (1.00-2.00) |
| AUCt (μg/mL*h) | 26.9 ± 8.53 |
| AUC (μg/mL*h) | 48.1 ± 6.49 |
| Vd (mL) | 9934 ± 3807 |
| CL (L/h) | 10.4 ± 1.77 |
| Kel (1/h) | 1.25 ± 0.66 |
| t1/2 (h) | 0.71 ± 0.35 |
# median (min-max)
Maximum plasma concentrations peaked at the end of the infusion period and declined thereafter with a rapid clearance and most of samples were undetectable 3.5 hours after the start of the infusion. Pharmacokinetic modelling simulation analysis showed that defibrotide plasma concentrations do not accumulate upon multiple dose administration and with doses up to 4-fold the therapeutic dose. Volume of distribution is around 10 L. In vitro studies demonstrate that 93% of defibrotide is bound to plasma proteins.
After administration of the therapeutic dose (6.25 mg/kg) to healthy subjects, an average of 9.48% of the total dose administered is excreted in urine as unchanged defibrotide in 24 hours, with the majority excreted during the first collection interval of 0-4 hours (approximately 98%).
Defibrotide does not inhibit or induce CYP450s.
Six patients with an estimated glomerular filtration rate <30 mL/min/1.73m² (calculated using the Modification of Diet in Renal Disease equation) and not currently on dialysis were compared to 6 healthy subjects with similar baseline demographics. Defibrotide 6.25 mg/kg was administered intravenously over 2 hours to subjects every 6 hours. Compared to healthy controls, subjects with renal impairment demonstrated 1.6- and 1.4-fold increases in AUC and Cmax, respectively and a half-life of about twice that of healthy subjects.
The amount of defibrotide excreted in urine over 24 hrs was about 5% of the total dose administered in those with renal impairment versus about 12% in healthy subjects.
Almost all renal excretion occurs within the first 4 hours. Accumulation of defibrotide over 4 doses was not found. Difference in exposure is not considered clinically relevant and so dose adjustment is not advised for patients with renal impairment.
In a sub-study it was shown that haemodialysis did not remove defibrotide.
No formal pharmacokinetic studies have been performed in hepatic impaired patients. Defibrotide has been used in clinical studies in patients with hepatic impairment without dose adjustment with no major safety issues identified.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenicity.
In both species, the main findings were accumulation of vacuolated macrophages in liver of dogs and in liver, kidneys and lymph nodes of rats. Macrophages are considered the main target organ.
In the Segment II reproductive studies in rats and rabbits, defibrotide has shown maternal toxicity by inducing a high rate of haemorrhagic abortion when infused intravenously over two hours at all dose levels tested including doses close to the human dose. Due to this maternal toxicity, no conclusion can be drawn regarding the effects of defibrotide on embryo-foetal development. PAI-2 is known to be uniquely up-regulated in the placenta.
Repeated intravenous administration of defibrotide, at doses below and close to the human therapeutic dose, to juvenile rats resulted in a delay in the mean age of preputial separation, suggesting a delay in the onset of male puberty in rats. However, the clinical relevance of these findings is unknown.
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