5
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      What is known about deferasirox chelation therapy in pediatric HSCT recipients: two case reports of metabolic acidosis

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          To date, in pediatric field, various hematological malignancies are increasingly treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Iron overload and systemic siderosis often occur in this particular cohort of patients and are associated with poor prognosis. We describe herein the case of two allo-HSCT patients, on treatment with deferasirox; they showed histopathological elements compatible with venoocclusive disease or vanishing bile duct syndrome in ductopenic evolution before deferasirox started. The first patient developed drug-induced liver damage with metabolic acidosis and the second one a liver impairment with Fanconi syndrome. After withdrawing deferasirox treatment, both patients showed improvement. Measurements of drug plasma concentrations were performed by HPLC assay. The reduction and consequent disappearance of symptoms after the suspension of deferasirox substantiate its role in inducing hepatic damage, probably enabling the diagnosis of drug-induced liver damage. But the difficulties in diagnosing drug-related toxicity must be underlined, especially in compromised subjects. For these reasons, in patients requiring iron-chelating therapy, close and careful drug therapeutic monitoring is strongly recommended.

          Related collections

          Most cited references 20

          • Record: found
          • Abstract: found
          • Article: not found

          Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalassemic patients with transfusion-dependent iron overload who are at pharmacokinetic steady state.

          Deferasirox (ICL670) is a novel once-daily, orally administered iron chelator to treat chronic iron overload in patients with transfusion-dependent anemias. Absorption, distribution, metabolism, and excretion of [14C]deferasirox at pharmacokinetic steady state was investigated in five adult beta-thalassemic patients. Deferasirox (1000 mg) was given orally once daily for 6 days to achieve steady state. On day 7, patients received a single oral 1000-mg dose (approximately 20 mg/kg) of [14C]deferasirox (2.5 MBq). Blood, plasma, feces, and urine samples collected over 7 days were analyzed for radioactivity, deferasirox, its iron complex Fe-[deferasirox]2, and metabolites. Deferasirox was well absorbed. Deferasirox and its iron complex accounted for 87 and 10%, respectively, of the radioactivity in plasma (area under the curve at steady state). Excretion occurred largely in the feces (84% of dose), and 60% of the radioactivity in the feces was identified as deferasirox. Apparently unchanged deferasirox in feces was partly attributable to incomplete intestinal absorption and partly to hepatobiliary elimination of deferasirox (including first-pass elimination) and of its glucuronide. Renal excretion was only 8% of the dose and included mainly the glucuronide M6. Oxidative metabolism by cytochrome 450 enzymes to M1 [5-hydroxy (OH) deferasirox, presumably by CYP1A] and M4 (5'-OH deferasirox, by CYP2D6) was minor (6 and 2% of the dose, respectively). Direct and indirect evidence indicates that the main pathway of deferasirox metabolism is via glucuronidation to metabolites M3 (acyl glucuronide) and M6 (2-O-glucuronide).
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Rust and corrosion in hematopoietic stem cell transplantation: the problem of iron and oxidative stress.

            Iron overload is a common acute and long-term event associated with autologous and allogeneic hematopoietic stem cell transplantation (HSCT). In a state of iron excess, free iron becomes available to catalyze the conversion of reactive oxygen species (ROS) intermediates such as superoxide anion (O2*-) and hydrogen peroxide (H2O2) to highly toxic free radicals such as hydroxyl radical (OH*). ROS may help to promote chronic liver disease, sinusoidal obstruction syndrome, idiopathic pneumonia syndrome and bacterial, fungal and other opportunistic infections. Phlebotomy has been effectively and safely used to deplete excess iron stores post-HSCT in thalassemic and other iron-overloaded patients. Intracellular iron levels may also be decreased through pharmacologic chelating agents, while antioxidants such as N-acetylcysteine, glutamine (glutathione precursor) and captopril have been shown to replenish glutathione redox potential and scavenge free radicals. A better understanding of the mechanisms involved in the iron-generated pro-oxidant state associated with HSCT will likely lead to reduced toxicity and improved patient outcomes.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Clinical pharmacology of deferasirox.

               Chiaki Tanaka (2014)
              Iron accumulation is a consequence of regular red cell transfusions, and can occur as a result of ineffective erythropoiesis secondary to increased intestinal iron absorption, in patients with various anemias. Without appropriate treatment, iron overload can lead to increased morbidity and mortality. Deferasirox is an oral iron chelator effective for reduction of body iron in iron-overloaded patients with transfusion-dependent anemias and non-transfusion-dependent thalassemia, with a well-established safety profile. This review summarizes the clinical pharmacokinetics, pharmacodynamics, and drug-drug interaction profile of deferasirox, and the claims supporting once-daily dosing for effective chelation. Sustained labile plasma iron suppression is observed with no rebound between doses, protecting organs from potential tissue damage. Increased iron excretion positively correlates with increased deferasirox exposure; to optimize iron removal transfusional iron intake, body iron burden and safety parameters should also be considered. Deferasirox dispersible tablets should be taken ≥30 min before food due to an effect of food on bioavailability. Dosing is consistent across pediatric and adult patients and there is no ethnic sensitivity. Dose adjustment is required for patients with hepatic impairment and may be considered upon coadministration with strong uridine diphosphate glucuronosyltransferase inducers or bile acid sequestrants (coadministration should be avoided where possible), and patients should be monitored upon coadministration with cytochrome P450 (CYP) 3A4/5, CYP2C8, or CYP1A2 substrates. Coadministration with hydroxyurea, a fetal hemoglobin modulator, does not appear to impact deferasirox pharmacokinetics. In summary, a substantial body of clinical and pharmacokinetic data are available for deferasirox to guide its optimal use in multiple patient populations and clinical circumstances.
                Bookmark

                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2018
                07 September 2018
                : 14
                : 1649-1655
                Affiliations
                [1 ]Pharmacology and Toxicology, Unit, University of Genoa, Genoa, Italy
                [2 ]Department of Pediatric Radiology, Institute for Maternal and Child Health – IRCCS Burlo Garofalo, Trieste, Italy
                [3 ]Department of Pathology, Ospedale Beato Papa Giovanni XIII, Bergamo, Italy
                [4 ]Bone Marrow Transplant Unit, Institute for Maternal and Child Health – IRCCS Burlo Garofalo, Trieste, Italy, natalia.maximova@ 123456burlo.trieste.it
                Author notes
                Correspondence: Natalia Maximova, Institute for Maternal and Child Health – IRCCS Burlo Garofolo, via dell’Istria 65/1, 34137 Trieste, Italy, Tel +39 40 378 5565, Fax +39 40 378 5494, Email natalia.maximova@ 123456burlo.trieste.it
                Article
                tcrm-14-1649
                10.2147/TCRM.S170761
                6136408
                © 2018 Fucile 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 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.

                Categories
                Case Series

                Comments

                Comment on this article