The pharmacokinetic and safety profile of single-dose deferiprone in subjects with sickle cell disease

Abstract Patients with sickle cell disease (SCD) who undergo repeated blood transfusions often develop iron overload. Deferiprone (Ferriprox®) is an oral iron chelator indicated for the treatment of transfusional iron overload due to thalassemia syndromes and has been recently approved as a treatment for iron overload in adult and pediatric patients with SCD and other anemias. The present study aims to characterize the pharmacokinetic (PK) profile of deferiprone (DFP) in adult subjects with SCD. In this phase I, open-label study, subjects with SCD were administered a single 1500 mg dose of DFP. Blood and urine samples were collected for PK assessments of DFP and its main metabolite, deferiprone 3-O-glucuronide (DFP-G). Eight subjects were enrolled and completed the study. Following drug administration, serum levels of DFP and DFP-G rose to maximum concentrations at 1.0 and 2.8 h post-dose, respectively. The half-lives of DFP and DFP-G were 1.5 and 1.6 h, respectively. The majority of administered drug was metabolized and excreted as DFP-G, with less than 4% excreted unchanged in urine up to 10 h post-dose. Subjects received a safety assessment 7 (± 3) days post-dose. Two subjects reported mild adverse events unrelated to the study drug, and no other safety concerns were reported. The PK profile of DFP in SCD subjects is consistent with previous reports in healthy adult volunteers, suggesting no special dosing adjustments are indicated for this population. These findings provide valuable insight for treating iron overload in patients with SCD, who have limited chelation therapy treatment options (trial registration number: NCT01835496, date of registration: April 19, 2013).

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Iron overload is a determinant of morbidity and mortality in adult patients with sickle cell disease

Seminars in Hematology ◽

10.1053/shem.2001.20142 ◽

2001 ◽

Vol 38 (1, Suppl 1) ◽

pp. 30-36 ◽

Cited By ~ 14

Author(s):

Samir K. Ballas

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Adult Patients ◽

Morbidity And Mortality ◽

Cell Disease

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Growth differentiation factor-15 in young sickle cell disease patients: Relation to hemolysis, iron overload and vascular complications

Blood Cells Molecules and Diseases ◽

10.1016/j.bcmd.2014.07.003 ◽

2014 ◽

Vol 53 (4) ◽

pp. 189-193 ◽

Cited By ~ 6

Author(s):

Azza Abdel Gawad Tantawy ◽

Amira Abdel Moneam Adly ◽

Eman Abdel Rahman Ismail ◽

Yasser Wagih Darwish ◽

Marwa Ali Zedan

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Vascular Complications ◽

Cell Disease ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor

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Serum ferritin and total units transfused for assessing iron overload in adults with sickle cell disease

British Journal of Haematology ◽

10.1111/j.1365-2141.2012.09060.x ◽

2012 ◽

Vol 157 (5) ◽

pp. 645-647 ◽

Cited By ~ 15

Author(s):

Emma Drasar ◽

Nisha Vasavda ◽

Norris Igbineweka ◽

Moji Awogbade ◽

Marlene Allman ◽

...

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Serum Ferritin ◽

Cell Disease

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Approaches to Transfusion Therapy and Iron Overload in Patients with Sickle Cell Disease: Results of an International Survey

Pediatric Hematology and Oncology ◽

10.3109/08880018.2010.505497 ◽

2010 ◽

Vol 28 (1) ◽

pp. 37-42 ◽

Cited By ~ 14

Author(s):

Elliott P. Vichinsky ◽

Kwaku Ohene-Frempong

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

International Survey ◽

Cell Disease ◽

Transfusion Therapy

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American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support

Blood Advances ◽

10.1182/bloodadvances.2019001143 ◽

2020 ◽

Vol 4 (2) ◽

pp. 327-355 ◽

Cited By ~ 22

Author(s):

Stella T. Chou ◽

Mouaz Alsawas ◽

Ross M. Fasano ◽

Joshua J. Field ◽

Jeanne E. Hendrickson ◽

...

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Guideline Development ◽

Practice Research ◽

Evidence Based ◽

Red Cell ◽

Cell Disease ◽

American Society

Background: Red cell transfusions remain a mainstay of therapy for patients with sickle cell disease (SCD), but pose significant clinical challenges. Guidance for specific indications and administration of transfusion, as well as screening, prevention, and management of alloimmunization, delayed hemolytic transfusion reactions (DHTRs), and iron overload may improve outcomes. Objective: Our objective was to develop evidence-based guidelines to support patients, clinicians, and other healthcare professionals in their decisions about transfusion support for SCD and the management of transfusion-related complications. Methods: The American Society of Hematology formed a multidisciplinary panel that was balanced to minimize bias from conflicts of interest and that included a patient representative. The panel prioritized clinical questions and outcomes. The Mayo Clinic Evidence-Based Practice Research Program supported the guideline development process. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to form recommendations, which were subject to public comment. Results: The panel developed 10 recommendations focused on red cell antigen typing and matching, indications, and mode of administration (simple vs red cell exchange), as well as screening, prevention, and management of alloimmunization, DHTRs, and iron overload. Conclusions: The majority of panel recommendations were conditional due to the paucity of direct, high-certainty evidence for outcomes of interest. Research priorities were identified, including prospective studies to understand the role of serologic vs genotypic red cell matching, the mechanism of HTRs resulting from specific alloantigens to inform therapy, the role and timing of regular transfusions during pregnancy for women, and the optimal treatment of transfusional iron overload in SCD.

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Serum Iron Levels and Copper-to-Zinc Ratio in Sickle Cell Disease

Medicina ◽

10.3390/medicina55050180 ◽

2019 ◽

Vol 55 (5) ◽

pp. 180

Author(s):

Charles Antwi-Boasiako ◽

Gifty Dankwah ◽

Robert Aryee ◽

Charles Hayfron-Benjamin ◽

Alfred Doku ◽

...

Keyword(s):

Oxidative Stress ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Serum Levels ◽

Zinc Homeostasis ◽

Healthy Controls ◽

Cell Disease ◽

Flame Atomic Absorption ◽

Iron Copper ◽

Copper And Zinc

Background and Objectives: Altered copper and zinc homeostasis may influence the antioxidant defense system and consequently lead to oxidative stress and associated complications in sickle cell disease (SCD) patients. Iron levels have been reported to increase in sickle cell patients due to frequent blood transfusion, chronic intravenous haemolysis and increased absorption of iron from the gastrointestinal tract. These elevated levels of iron may also lead to extensive oxidative damage. The current study evaluated serum levels of iron, copper and zinc in SCD patients and “healthy” controls. Materials and Methods: The study was a cross-sectional one, comprising 90 SCD patients with Haemoglobin SS and Haemoglobin SC genotypes and 50 HbAA “healthy” controls. Serum levels of iron, copper and zinc were measured using a Flame Atomic Absorption Spectrometer (Variant 240FS manufactured by VARIAN Australia Pty Ltd, VIC, Australia). Copper and zinc ratios were calculated and analyzed. Results: Serum levels of iron and copper were significantly elevated in the SCD patients, compared to their “healthy” counterparts (p < 0.001). These levels were further increased in patients with haemoglobin SS in vaso-occlusive crises (HbSS VOCs). Serum zinc levels were, however, significantly lower in the SCD patients, particularly during vaso-occlusion. The copper-to-zinc ratio was also found to be significantly higher in the SCD patients. Conclusion: Elevated copper-to-zinc ratio may be a biomarker of sickle cell oxidative stress and associated complications. The ratio may also be informative for the management of sickle cell oxidative burden. The significantly lower levels of zinc in the SCD patients may warrant zinc supplementation.

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Iron Depletion: An Ameliorating Factor for Sickle Cell Disease?

ISRN Hematology ◽

10.5402/2011/473152 ◽

2011 ◽

Vol 2011 ◽

pp. 1-4 ◽

Cited By ~ 5

Author(s):

P. C. Giordano ◽

W. Huisman ◽

C. L. Harteveld

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Beneficial Effect ◽

Sickle Cell ◽

Chelation Therapy ◽

Cell Disease ◽

Laboratory Practice ◽

Iron Depletion ◽

Severity Of The Disease

We report some observations from our laboratory practice that might be important for the treatment of sickle cell disease (SCD). We describe data from two cases indicating that iron depletion might have a beneficial effect diminishing the formation of HbS in favor of HbF, possibly reducing the severity of the disease. We believe that it would be worthwhile to monitor the course of the disease comparing cases with identical genotypes with and without iron depletion, and we advise to consider chelation therapy to reduce iron overload in patients with SCD.

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Increased levels of soluble P-selectin correlate with iron overload in sickle cell disease

British Journal of Biomedical Science ◽

10.1080/09674845.2007.11732771 ◽

2007 ◽

Vol 64 (3) ◽

pp. 124-126 ◽

Cited By ~ 1

Author(s):

A.D. Blann ◽

S.S. Marwah ◽

A.J. Cobley ◽

D Bareford

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Cell Disease ◽

Soluble P

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Consequences and management of iron overload in sickle cell disease

Hematology ◽

10.1182/asheducation-2013.1.447 ◽

2013 ◽

Vol 2013 (1) ◽

pp. 447-456 ◽

Cited By ~ 57

Author(s):

John Porter ◽

Maciej Garbowski

Keyword(s):

Sickle Cell Disease ◽

Blood Transfusion ◽

Iron Overload ◽

Sickle Cell ◽

Iron Concentration ◽

Thalassemia Major ◽

Iron Loading ◽

Cell Disease ◽

Liver Iron Concentration ◽

Liver Iron

Abstract The aims of this review are to highlight the mechanisms and consequences of iron distribution that are most relevant to transfused sickle cell disease (SCD) patients and to address the particular challenges in the monitoring and treatment of iron overload. In contrast to many inherited anemias, in SCD, iron overload does not occur without blood transfusion. The rate of iron loading in SCD depends on the blood transfusion regime: with simple hypertransfusion regimes, rates approximate to thalassemia major, but iron loading can be minimal with automated erythrocyte apheresis. The consequences of transfusional iron overload largely reflect the distribution of storage iron. In SCD, a lower proportion of transfused iron distributes extrahepatically and occurs later than in thalassemia major, so complications of iron overload to the heart and endocrine system are less common. We discuss the mechanisms by which these differences may be mediated. Treatment with iron chelation and monitoring of transfusional iron overload in SCD aim principally at controlling liver iron, thereby reducing the risk of cirrhosis and hepatocellular carcinoma. Monitoring of liver iron concentration pretreatment and in response to chelation can be estimated using serum ferritin, but noninvasive measurement of liver iron concentration using validated and widely available MRI techniques reduces the risk of under- or overtreatment. The optimal use of chelation regimes to achieve these goals is described.

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