Pharmacokinetic profile of defibrotide in patients with renal impairment

Tocchetti, Paola; Tudone, Elena; Marier, Jean‐François; Marbury, Thomas; Zomorodi, Katie; Eller, Mark G.

doi:10.2147/dddt.s112181

Cited by 14 publications

(14 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Elimination occurs primarily via urine [65]. Defibrotide does not appear to accumulate after multiple doses in animals or in healthy or renally impaired subjects [65,66] and is not cleared by hemodialysis [66]. These findings support defibrotide prescribing guidance stating no dose adjustment is necessary for hemodialysis or severe/end-stage renal disease.…”

Section: Drug Evaluationmentioning

confidence: 82%

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.

View full text Add to dashboard Cite

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...

show abstract

Section: Drug Evaluationmentioning

confidence: 82%

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.

View full text Add to dashboard Cite

show abstract

“…Primarily during the first 4 h following administration of defibrotide 6.25-15 mg/kg doses as 2-h infusions, approximately 5-15% of the total dose is excreted in urine unmetabolized [39]. There is no apparent accumulation of defibrotide after multiple doses in animals, healthy volunteers, and patients with renal impairment [54,55]. Defibrotide is not cleared by intermittent hemodialysis [55].…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

“…There is no apparent accumulation of defibrotide after multiple doses in animals, healthy volunteers, and patients with renal impairment [54,55]. Defibrotide is not cleared by intermittent hemodialysis [55]. Table 3 summarizes the results from the early-phase clinical studies of defibrotide for the treatment of patients with post-HSCT hepatic VOD/SOS.…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

Defibrotide for children and adults with hepatic veno-occlusive disease post hematopoietic cell transplantation

Corbacioglu

Richardson

2017

Expert Review of Gastroenterology & Hepatology

View full text Add to dashboard Cite

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a complication that is typically associated with conditioning for hematopoietic stem cell transplantation (HSCT). In patients with concomitant multi-organ dysfunction, mortality may be >80%. Recently, the European Society for Blood and Marrow Transplantation established separate criteria for diagnosis and severity of VOD/SOS for adults and children, to better reflect current understanding of the disease. Areas covered: This review provides an overview of post-HSCT hepatic VOD/SOS and defibrotide, including its pharmacological, clinical, and regulatory profile. In children and adults following HSCT, defibrotide is approved for the treatment of hepatic VOD/SOS with concomitant renal or pulmonary dysfunction in the United States and for the treatment of severe hepatic VOD/SOS in the European Union. Day +100 survival rates with defibrotide are superior to those of historical controls receiving best supportive care only, and safety profiles are similar. Expert commentary: Defibrotide appears to act through multiple mechanisms to restore thrombo-fibrinolytic balance and protect endothelial cells, and there are promising data on the use of defibrotide for VOD/SOS prophylaxis in high-risk children undergoing HSCT. An ongoing randomized controlled trial in children and adults will better assess the clinical value of defibrotide as a preventive medication.

show abstract

“…A single 6.25 mg/kg dose of defibrotide given as a 2-h infusion in healthy subjects has a time to maximum plasma concentration (T max ) of 2 h [64], a half-life of 43 min [65], and does not affect cytochrome P450 metabolism [65]. An average of 93% of defibrotide is bound to human plasma protein, and the volume of distribution ranges from 8.1 to 9.1 [3].…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

“…Approximately 5% to 15% of the total dose is excreted in the urine unmetabolized [3]. No accumulation of defibrotide was seen after multiple doses in animals, healthy volunteers, or in patients with renal impairment [52,64]. Defibrotide is not cleared by intermittent hemodialysis [64].…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

Recent developments with defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome

Duncan

Kahn

Grupp

et al. 2019

Expert Opinion on Orphan Drugs

View full text Add to dashboard Cite

Introduction: Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening condition associated with endothelial cell damage due to hematopoietic cell transplantation (HCT) conditioning or chemotherapy not associated with HCT. Defibrotide is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post-HCT in the United States and Canada, and severe hepatic VOD/SOS in patients aged >1 month in the European Union. Areas covered: VOD/SOS results from prolonged endothelial cell activation from exposure to chemotherapy or radiotherapy. PubMed was searched for articles on defibrotide without publication date restrictions. In vitro evidence suggests defibrotide has a protective effect on endothelial cells. The efficacy of defibrotide for the treatment of VOD/SOS with multi-organ dysfunction has been shown in clinical trials. Defibrotide has a favorable safety profile comparable to best supportive care in patients with severe forms of VOD/SOS. Expert opinion: As defibrotide treatment for VOD/SOS is most effective when initiated early, medical teams should familiarize themselves with the risk factors for VOD/SOS development and be able to recognize early signs and symptoms. Preclinical data indicate that defibrotide has a protective effect on endothelial cells that may contribute to its efficacy in VOD/SOS and that may render the drug applicable for other indications.

show abstract

Pharmacokinetic profile of defibrotide in patients with renal impairment

Cited by 14 publications

References 35 publications

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

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

Defibrotide for children and adults with hepatic veno-occlusive disease post hematopoietic cell transplantation

Recent developments with defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome

Contact Info

Product

Resources

About