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Pharmacokinetic Profile of Defibrotide in Patients with Renal Impairment

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Pharmacokinetic Profile of Defibrotide in Patients with Renal Impairment Journal name: Drug Design, Development and Therapy Article Designation: Clinical Trial Report Year: 2016 Volume: 10 Drug Design, Development and Therapy Dovepress Running head verso: Tocchetti et al Running head recto: Pharmacokinetic profile of defibrotide in renal impairment open access to scientific and medical research DOI: http://dx.doi.org/10.2147/DDDT.S112181 Open Access Full Text Article CLINICAL TRIAL REPORT Pharmacokinetic profile of defibrotide in patients with renal impairment Paola Tocchetti1 Abstract: Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/ Elena Tudone2 SOS), is an unpredictable, potentially life-threatening complication of hematopoietic stem cell Jean-Francois Marier3 transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction Thomas C Marbury4 (pulmonary or renal dysfunction), may be associated with .80% mortality. Defibrotide, recently Katie Zomorodi5 approved in the US, has demonstrated efficacy treating hepatic VOD/SOS with multiorgan Mark Eller6 dysfunction. Because renal impairment is prevalent in patients with VOD/SOS, this Phase I, open-label, two-part study in adults examined the effects of hemodialysis and severe or end-stage 1 2 Gentium, Clinical Operations, renal disease (ESRD) on defibrotide pharmacokinetics (PK). Part 1 compared defibrotide PK Gentium, Villa Guardia, Como, Italy; 3Reporting and Analysis Services, during single 6.25 mg/kg doses infused with and without dialysis. Part 2 assessed defibrotide Pharsight, a Certara Company, plasma PK after multiple 6.25 mg/kg doses in nondialysis-dependent subjects with severe/ Montreal, Quebec, Canada; 4Orlando ESRD versus healthy matching subjects. Among six subjects enrolled in Part 1, percent ratios Clinical Research Center, Orlando, FL, 5 For personal use only. Early Development and Clinical of least-squares mean and 90% confidence intervals (CIs) on dialysis and nondialysis days Pharmacology, Jazz Pharmaceuticals, were 109.71 (CI: 97.23, 123.78) for maximum observed plasma concentration (C ); 108.39 6Early Drug Development, Jazz max Pharmaceuticals, Palo Alto, CA, USA (CI: 97.85, 120.07) for area under the concentration–time curve to the time of the last quantifi- able plasma concentration (AUC0–t); and 109.98 (CI: 99.39, 121.70) for AUC extrapolated to infinity (AUC0–∞). These ranges were within 80%–125%, indicating no significant effect of dialysis on defibrotide exposure/clearance. In Part 2, defibrotide exposure parameters in six sub- jects with severe/ESRD after multiple doses (AUC0–t, 113 µg⋅h/mL; AUC over dosing interval, 113 µg⋅h/mL; Cmax, 53.8 µg/mL) were within 5%–8% of parameters after the first dose (AUC0–t, 117 µg⋅h/mL; AUC0–∞, 118 µg⋅h/mL; Cmax, 54.9 µg/mL), indicating no accumulation. Defibrot- ide peak and extent of exposures in those with severe/ESRD were ~35%–37% and 50%–60% higher, respectively, versus controls, following single and multiple doses. One adverse event (vomiting, possibly drug-related) was reported. These findings support defibrotide prescribing guidance stating no dose adjustment is necessary for hemodialysis or severe/ESRD. Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 12-Dec-2018 Keywords: dialysis, end-stage renal disease, hepatic veno-occlusive disease, sinusoidal obstruction syndrome Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/ SOS), is a potentially fatal complication of the conditioning regimen for hematopoietic stem cell transplantation (HSCT).1,2 Clinical characteristics include hepatomegaly and/or right upper quadrant pain, ascites, otherwise unexplained weight gain, and jaundice.1–3 Diagnosis is clinical and generally made according to a set of pre- defined signs/symptoms: the Baltimore criteria (presence, within 21 days of HSCT, Correspondence: Paola Tocchetti Biologa Nutrizionista, Via F Marchesoli 3, of bilirubin $2 mg/dL plus two or more of the following: hepatomegaly, ascites, 22100 Como, Italy weight gain $5%)4 or the modified Seattle criteria (presence, within 20 days of Tel +39 347 431 6587 Email [email protected] HSCT, of two or more of the following: bilirubin .2 mg/dL, hepatomegaly or right submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2016:10 2631–2641 2631 Dovepress © 2016 Tocchetti et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/DDDT.S112181 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Tocchetti et al Dovepress upper quadrant pain, and/or .2% weight gain, sometimes HSCT.21,22 Defibrotide is also recommended as first-line further modified as .5%).5 Although increased bilirubin treatment of VOD/SOS by the European Society for Blood is a component of both sets of criteria, recent data indicate and Marrow Transplantation,19 based on clinical Phase II/III that this sign may be absent in some cases of VOD/SOS, study data in HSCT patients with VOD/SOS and MOD23,24 particularly in children, and in adult patients with relatively and for VOD/SOS prevention and treatment by the British late-developing VOD/SOS.6–9 Committee for Standards in Haematology/British Society of The reported prevalence of VOD/SOS following HSCT Blood and Marrow Transplantation (strength of recommen- has varied widely, with a mean incidence of 13.7% (range dation: strong; quality of evidence: high, except moderate 0%–62.3%), as determined by a meta-analysis of 135 studies.10 for prevention in adults),14 based on clinical Phase II/III data The same meta-analysis also found that mean VOD/SOS inci- in HSCT patients at risk for VOD/SOS.7,23,24 dence had increased from 11.5% during the period of 1979 In vitro evidence suggests that defibrotide protects and to 1994 to 14.6% from 1994 to 2007; although the reasons stabilizes endothelial cells through antithrombotic, profi- for this elevation were unclear, it may be due to increased brinolytic, and anti-inflammatory actions, and restores the awareness of the disease.10 In contrast, single-center studies endothelial thrombo-fibrinolytic balance.25–30 Because of defi- in patients receiving HSCT during the time period since the brotide’s demonstrated efficacy in the treatment of hepatic late 1990s have reported VOD/SOS prevalence of ~6.5% VOD/SOS with MOD (including renal dysfunction),15,23,31 to 9%, suggesting that risk reduction measures, such as evidence of tolerability in other conditions,32–34 and the high decreased intensity of the conditioning regimen, may have prevalence of renal impairment in patients with VOD/SOS, reduced the incidence of VOD/SOS, although it remains a a two-part study was conducted to assess the pharmacoki- serious complication after HSCT.11–13 netics (PK) of defibrotide in renal-impaired subjects. The Severe VOD/SOS is typically associated with multiorgan primary trial objectives were: (Part 1) to investigate the dysfunction (MOD), including dysfunction of the kidneys, effects of hemodialysis on defibrotide PK, chiefly whether lungs, and/or heart.1,10,14 At study entry of the Phase III trial defibrotide is cleared by dialysis, in subjects with end-stage For personal use only. of defibrotide for patients with VOD/SOS and MOD, for renal disease (ESRD) receiving intermittent hemodialysis; example, 20% of patients in the treatment arm were dialysis- and (Part 2) to compare the plasma PK profile of defibrotide dependent.15 Severe VOD/SOS is also associated with a in subjects with severe renal disease/ESRD not dependent on mortality rate .80%.10 Development of severe VOD/SOS dialysis with that in healthy matching subjects. Secondary is often unpredictable; reported incidence has ranged from objectives were to evaluate the general safety and tolerability 0% to 77% of all patients with VOD/SOS in specific study profile of defibrotide in renal-impaired subjects. populations and depending on the size of the population Careful evaluation of the effects of kidney disease in sub- studied.10,12,13,16 In allogeneic HSCT, up to 48% of VOD/SOS jects with varying degrees of renal dysfunction, including those cases diagnosed by Baltimore criteria have been reported to on hemodialysis (the most common renal replacement method be VOD/SOS with MOD.11 used in patients with ESRD), on drug PK is recommended by VOD/SOS pathophysiology appears to stem initially from the FDA35 and the European Medicines Agency.36 Impaired Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 12-Dec-2018 extensive injury to sinusoidal endothelial cells, hepatocytes, renal function often leads to drug accumulation, requiring dose and stellate cells, triggering a pathophysiologic cascade reduction to minimize toxicity; on the other hand, dialysis may involving venular microthrombosis, fibrin deposition, isch- remove drugs from the body, possibly below the therapeutic emia, fibrogenesis, portal hypertension, and hepatorenal plasma threshold and thus
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