Drug safety evaluation of defibrotide

Richardson, Paul G.; Corbacioglu, Selim; Ho, Vincent T.; Kernan, Nancy A.; Lehmann, Leslie; Maguire, Craig; Maglio, Michelle E.; Hoyle, Margaret; Sardella, M; Giralt, Sergío; Holler, Ernst; Carreras, Enric; Niederwieser, Dietger; Soiffer, Robert J.

doi:10.1517/14740338.2012.749855

Cited by 71 publications

(101 citation statements)

References 61 publications

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“…22 However, defibrotide has demonstrated no significant systemic anticoagulant effects in pharmacologic studies. 4,11,15,23 Findings of in vitro and animal studies suggest that defibrotide may protect EC from toxic, inflammatory, and reperfusion damage; reduce activation of EC; and modulate their function. 4,18,[24][25][26][27][28] In combination, these effects appear to promote an anticoagulant phenotype specific to the endothelium.…”

Section: Key Pharmacologic Actions and Characteristicsmentioning

confidence: 99%

The use of defibrotide in blood and marrow transplantation

et al. 2018

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propensity analysis-estimated between-group difference: 23%; P 5 .0109). The most common adverse events (AEs) were hypotension and diarrhea; rates of common hemorrhagic AEs were similar in the defibrotide and historical control group (64% and 75%, respectively). In a phase 3 prophylaxis trial, defibrotide was found to lower incidence of VOD/SOS in children (not an approved indication) and reduce the incidence of graftversus-host disease. This review describes the development and clinical applications of defibrotide, focusing on its on-label use in patients with VOD/SOS and MOD/MOF after HSCT.

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Section: Key Pharmacologic Actions and Characteristicsmentioning

confidence: 99%

The use of defibrotide in blood and marrow transplantation

et al. 2018

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“…Overall, the incidence of defibrotide TRAEs was found to be 6% in a 2013 drug safety evaluation of defibrotide, which reviewed data for 1824 pediatric and adult HSCT patients who had received defibrotide for treatment or prophylaxis of VOD/ SOS [63,81]. As expected, the rate of AEs assessed as at least possibly defibrotide related was highest in patients with VOD/SOS and MOF, associated with illness and comorbidities, and lowest in those receiving defibrotide prophylaxis.…”

Section: Safety and Tolerability Summarymentioning

confidence: 92%

“…Further, defibrotide is antithrombotic without having significant systemic anticoagulant effects [56,60], although patients should be monitored for bleeding [61][62][63]. In a study that looked into an association between HPSE SNPs and hepatic VOD/SOS in children undergoing allogeneic HSCT, 12 of 160 patients (8%) were diagnosed with VOD/SOS using the modified Seattle criteria [25] and treated with defibrotide.…”

Section: Drug Evaluationmentioning

confidence: 99%

Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multiorgan Failure

Richardson

Grupp

Pagliuca

et al. 2017

Int. J. Hematol. Oncol.

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Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening and unpredictable complication of hematopoietic stem cell transplantation (HSCT). Characterized by a prothrombotic-hypofibrinolytic state, VOD/SOS typically presents with hyperbilirubinemia, ascites, weight gain and painful hepatomegaly; VOD/SOS with multiorgan failure may be associated with >80% mortality. Treatment has been mainly supportive. However, defibrotide is now approved in the USA for treatment of hepatic VOD/SOS with renal or pulmonary dysfunction following HSCT and in the EU for treatment of severe hepatic VOD/SOS post-HSCT. In vitro evidence suggests defibrotide may restore thrombotic-fibrinolytic balance at the endothelial level and protect endothelial cells. Defibrotide has demonstrated significant reduction in VOD/SOS-related mortality and resolved VOD/SOS-related symptoms, with a manageable safety profile. KEYWORDS• defibrotide • diagnostic criteria • efficacy • mechanism of action • multiorgan dysfunction • pathophysiology • safety • sinusoidal obstruction syndrome • treatment • veno-occlusive disease Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening and unpredictable complication of toxic injury mainly from conditioning regimens for hematopoietic stem cell transplantation (HSCT) [1,2]. Although less common, VOD/SOS also may develop as a result of primary chemotherapy, immunotoxin conjugated therapies or radiation, particularly in children [1][2][3][4]. Mean prevalence of VOD/SOS among post-HSCT patients was estimated to be 13.7% (95% confidence interval [CI] = 13.3-14.1%), based on a review of 135 studies, each conducted in more than 50 patients between 1979 and 2007 [5]. VOD/SOS with multiorgan failure (MOF; also sometimes referred to as multiorgan dysfunction) occurs in an estimated 30-40% of patients with VOD/SOS after HSCT [6], and carries a mortality rate that exceeds 80% [5]. Children differ substantially from adults, with an incidence of VOD/ SOS approximately two-to three-fold higher overall [4,[7][8][9], and rates as high as 30-60% in highrisk subpopulations like infants and those with inherited diseases like familial hemophagocytic lymphohistiocytosis, thalassemia [10] and osteopetrosis [7,11,12]. Clinical presentation also differs in children, who often lack hyperbilirubinemia [4,7,13,14], the hallmark of VOD/SOS. Development of VOD/SOS after HSCT involves a complex pathophysiologic cascade initiated by the toxic injury from the conditioning regimen, with subsequent endothelial-cell damage and activation, and a prothrombotichypofibrinolytic state leading to central venous occlusion and/or sinusoidal obstruction [1,15,16]. The initial toxic injury occurs to sinusoidal endothelial cells and hepatocytes in zone 3 of the liver acinus. Because endothelial cells help regulate the equilibrium between pro-and antithrombotic factors, their injury may lead to progressive deterioration of thrombofibrino...

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“…[1][2][3] Several functions, specially related to hemostasis, have been ascribed to DF. 4 In this regard, our group has demonstrated the protective effect of DF on the endothelium, by preventing the endothelial damage associated with hematopoietic cell transplantation (HCT) conditions, 5,6 and with the deleterious effect of immunosuppresants.…”

Section: Introductionmentioning

confidence: 99%

What is going on between defibrotide and endothelial cells? Snapshots reveal the hot spots of their romance

Palomo

Mir

Rovira

et al. 2016

Blood

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Key Points• Specific interaction of DF with EC membranes is followed by its internalization mainly through macropinocytic mechanisms.• DF attachment to the cell membrane is sufficient to perform its antiinflammatory and antioxidant effects on the endothelium.Defibrotide (DF) has received European Medicines Agency authorization to treat sinusoidal obstruction syndrome, an early complication after hematopoietic cell transplantation. DF has a recognized role as an endothelial protective agent, although its precise mechanism of action remains to be elucidated. The aim of the present study was to investigate the interaction of DF with endothelial cells (ECs). A human hepatic EC line was exposed to different DF concentrations, previously labeled. Using inhibitory assays and flow cytometry techniques along with confocal microscopy, we explored: DF-EC interaction, endocytic pathways, and internalization kinetics. Moreover, we evaluated the potential role of adenosine receptors in DF-EC interaction and if DF effects on endothelium were dependent of its internalization.Confocal microscopy showed interaction of DF with EC membranes followed by internalization, though DF did not reach the cell nucleus even after 24 hours. Flow cytometry revealed concentration, temperature, and time dependent uptake of DF in 2 EC models but not in other cell types. Moreover, inhibitory assays indicated that entrance of DF into ECs occurs primarily through macropinocytosis. Our experimental approach did not show any evidence of the involvement of adenosine receptors in DF-EC interaction. The antiinflammatory and antioxidant properties of DF seem to be caused by the interaction of the drug with the cell membrane. Our findings contribute to a better understanding of the precise mechanisms of action of DF as a therapeutic and potential preventive agent on the endothelial damage underlying different pathologic situations. (Blood. 2016;127(13):1719-1727 Introduction Defibrotide (DF) is a mixture of 90% single-stranded phosphodiester oligonucleotides (length, 9-80 mer; average molecular mass, 16.5 6 2.5 KDa) and 10% double-stranded phosphodiester oligonucleotides, derived from the controlled depolymerization of porcine intestinal mucosal DNA.1-3 Several functions, specially related to hemostasis, have been ascribed to DF. 4 In this regard, our group has demonstrated the protective effect of DF on the endothelium, by preventing the endothelial damage associated with hematopoietic cell transplantation (HCT) conditions, 5,6 and with the deleterious effect of immunosuppresants. 7 In our in vitro endothelial activation model, DF has exhibited reproducible effects on endothelial cells (ECs) from different origins. DF demonstrates antiinflammatory, antithrombotic, and antiapoptotic properties. However, although its effects are increasingly better understood, its precise mechanism of action remains to be elucidated.There is limited knowledge about DF pharmacokinetics, pharmacodynamics, and mechanisms of action. [8][9][10] However, 2 distinct properties of ...

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Drug safety evaluation of defibrotide

Abstract: DF was well tolerated in majority of the studies. The safety profile of DF is largely favourable with toxicities comparable to control populations in the setting of SCT complicated by sVOD.

Cited by 71 publications

References 61 publications

The use of defibrotide in blood and marrow transplantation

The use of defibrotide in blood and marrow transplantation

Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multiorgan Failure

What is going on between defibrotide and endothelial cells? Snapshots reveal the hot spots of their romance

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