Drotrecogin alfa

 

Information about Drotrecogin alfa

Defibrotide is a complex mixture of single stranded polydeoxyribonucleotides derived from porcine intestinal mucosa that has antithrombotic and profibrinolytic activity and is used in the treatment of severe sinusoidal obstruction syndrome (SOS) after hematopoietic cell transplantation (HCT).  Defibrotide is used in patients with severe liver injury and has not been associated with worsening of serum aminotransferase elevations during therapy and has not been linked to cases of clinically apparent, idiosyncratic liver injury.

Mechanism of action of Drotrecogin alfa

Defibrotide (de fib' roe tide) is a mixture of single stranded molecules of polydeoxyribonucleotides derived from porcine intestinal mucosa with molecular weights between 15,000 and 30,000 daltons.  The short, single stranded DNA molecules have antithrombotic and profibrinolytic activities which suggested their use to treat SOS occurring after myeloablative regimens given in preparation of HCT.  However, the pathophysiology of SOS involves destruction of sinusoidal endothelial centers in centrolobular (zone 3) regions along with stellate cell activation and deposition of collagen in sinusoids, and not thrombus formation.  Thus, the mechanism of action of defibrotide in severe SOS is unknown, but it appears to act as an adenosine receptor agonist and as a stimulus to the production of endogenous prostaglandins, both of which modulate thrombogenesis and fibrinolysis.  Defibrotide also binds to endothelial cells and may have cytoprotective activities on sinusoid cells or modulating effects on stellate cells.  In multiple open label clinical trials, defibrotide was found to improve recovery of serum bilirubin elevations in SOS, but only in comparison to historical controls.  Despite the lack of prospective, randomized controlled trials, defibrotide was approved for use in the United States in 2016 for severe SOS accompanied by evidence of renal or pulmonary failure occurring after myeloablation in preparation for HCT.  Defibrotide is available as a solution for injection in single use vials of 200 mg/2.5 mL (80 mg/mL) under the brand name Defitelio. 

Dosage and administration for Drotrecogin alfa

The recommended dose is 6.25 mg/kg every 6 hours for at least 21 days.  Side effects include bleeding, hypotension, diarrhea, nausea and abdominal pain, but the typical patient receiving defibrotide is often critically ill with multiorgan failure and severe liver injury.  Thus, minor and even fairly major side effects of defibrotide would be difficult to link to this therapy as opposed to the underlying severe, acute injury. 

• Dailymed label info on Drotrecogin alfa
• FDA Drotrecogin alfa