A Dose Escalation Study of the Pharmacokinetics, Safety & Efficacy of Deferitrin, an Oral Iron Chelator in Beta Thalassaemia Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2669-2669 ◽  
Author(s):  
R. Galanello ◽  
G. Forni ◽  
A. Jones ◽  
A. Kelly ◽  
A. Willemsen ◽  
...  
Keyword(s):  
Quantum Interference ◽  
Renal Toxicity ◽  
Iron Concentration ◽  
Iron Chelator ◽  
Iron Accumulation ◽  
Iron Intake ◽  
Post Dose ◽  
Once Daily ◽  
Beta Thalassaemia ◽  
Iron Excretion

Abstract Iron accumulation and overload in beta thalassaemia patients are associated with significant morbidity and mortality. Iron chelators are used to manage iron accumulation but side effects and compliance issues restrict the use of available chelators. Deferitrin (Genzyme Corporation) is an orally available iron chelator intended for iron overload. Method: Patients were dosed in 4 cohorts, receiving 5, 10, 15 and 25 mg/kg/day of deferitrin. Deferitrin dosing in cohorts 1–3 was once daily for 12 weeks. Cohort 4 received deferitrin twice daily (BD) for 48 weeks (12.5mg/kg BD, 25 mg/kg/day). Pharmacokinetics (PK) were assessed in a subset of up to 5 patients in each cohort, pre-dose and 1, 2, 4 and 8 hours post dose. All patients had trough levels assessed at weeks 1, 6 and 12 (all Cohorts) and additionally at weeks 24, 36 and 48 for Cohort 4. PK parameters were determined by model independent (non-compartmental) analyses. Safety was assessed by collection of adverse events and laboratory assessments with renal parameters measured weekly due to observations of renal toxicity in preclinical testing. Efficacy (change in liver iron concentration (LIC)) was assessed by SQUID (superconducting quantum interference device) in Turin, Italy, between screening and end of study. Iron excretion and intake were estimated by calculation:Iron excretion due to deferitrin = Iron Intake (mg/kg/day) - TBI (mg/kg/day)Iron Intake (mg/kg/day) = [total mL pRBC (exclude last BT×) × 1.08] / [Weight (kg) × Days (Between 1st & last BT×)]TBI (mg/kg/day) = Change in LIC (mg Fe/g dry weight) × [10.6 (Angelucci Factor) / D (Days on deferitrin)] Key: pRBC = packed red blood cells, BT× = blood transfusion, TBI=Total Body Iron. Results: PK: PK for deferitrin dosed once daily was linear and dose proportional. The serum half-life was 1.3–1.8 hrs, clearance was 226–340 mL/min and mean residence time was 2.8–3.4 hrs for once daily dosing. PK data from BD dosing is not yet available. Safety: Deferitrin dosed once daily was generally well tolerated (Cohorts 1–3). Slight rises in transaminases were seen at 10 and 15 mg/kg/day. A large proportion of enrolled patients were hepatitis C positive (73%). When dosed BD (12.5 mg/kg BD in Cohort 4), 3 patients developed renal toxicity after 4–5 weeks of treatment. Two patients experienced increased proteinuria (max 3.73 g/L & 3.29 g/L) and one patient suffered acute renal failure (peak serum creatinine 4.1 mg/dL, lowest GFR 27 mmol/L). All patients recovered normal renal function after stopping treatment. No patients were re-challenged with deferitrin. Dosing was terminated in all patients because of safety concerns. Efficacy: Mean iron excretion in mg/kg/day (S.D) for Cohort 1 was 0.22 (0.22), Cohort 2 was 0.45 (0.14) and Cohort 3 was 0.33 (0.12). The reasons for the lack of dose proportionality in iron excretion are unclear. Efficacy could not be assessed in Cohort 4 due to early termination of the study. Conclusions: Deferitrin dosed once daily was generally well tolerated and associated with a mean iron excretion of 0.34 mg/kg/day. Deferitrin dosed BD (12.5mg/kg BD) was associated with unacceptable renal toxicity and led to study termination. Deferitrin does not appear to have an acceptable therapeutic margin to allow sufficient iron excretion for long-term administration.

Iron Chelation Efficiency of Deferasirox (Exjade®, ICL670) in Patients with Transfusional Hemosiderosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2690-2690 ◽  
Author(s):  
J. Porter ◽  
C. Borgna-Pignatti ◽  
M. Baccarani ◽  
A. Saviano ◽  
S. Abish ◽  
...  
Keyword(s):  
Binding Capacity ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Iron Chelator ◽  
Tridentate Ligand ◽  
Average Dose ◽  
Iron Intake ◽  
Liver Iron ◽  
Molecular Weights ◽  
Iron Excretion

Abstract Iron excretion can be calculated according to Angelucci et al (NEJM 2000). As applied to the novel oral iron chelator deferasirox (DSX), chelation efficiency can then be determined as the % iron excretion vs theoretical iron binding capacity of chelator dose: % efficiency = [iron excretion (mg/kg/day)/chelator dose (mg/kg/day)] x [374/56] x 2 x 100 (374 and 56 represent the molecular weights of DSX and iron; factor 2 accounts for the tridentate ligand). In a total of 325 patients with β-thalassemia (n=285) or rare anemias, such as MDS (n=13), DBA (n=14) or other anemias (n=13), included in the DSX Phase II and III Studies 0108 and 0107, liver iron concentration (LIC) was evaluated by liver biopsy at baseline and study end. All patients were treated with once-daily oral DSX 5, 10, 20 or 30 mg/kg according to baseline LIC (2–3, >3–7, >7–14 and >14 mg Fe/g dw, respectively). In these patients, the average dose during study was 22.8 ± 7.6 mg/kg. The average iron intake was 0.37 mg/kg/day and was similar between dose cohorts. Efficiency of daily DSX treatment (mean ± SD) Baseline LIC 2–3 >3–7 >7–14 >14 DSX, mg/kg 5 (n=9) 10 (n=49) 20 (n=81) 30 (n=186) Iron excretion (mg/kg/day) 0.14 ± 0.1 0.21 ± 0.1 0.39 ± 0.1 0.57 ± 0.2 Iron intake (mg/kg/day) 0.39 ± 0.1 0.37 ± 0.1 0.38 ± 0.1 0.36 ± 0.1 Ratio iron excretion/intake 0.33 ± 0.2 0.53 ± 0.4 1.09 ± 0.5 1.66 ± 0.8 Efficiency (%) 31.6 ± 26.4 27.5 ± 18.4 27.1 ± 10.3 27.3 ± 12.4 There were no differences in the chelation efficiency of DSX between the overall initial dose groups, and thus between different LIC categories at baseline, or between age and disease groups. Using the estimated efficiency of 27%, and the formula above, the approximate dose (mg) needed to achieve iron balance corresponds to an iron intake in mg Fe/kg/day divided by 0.02. For a patient receiving 0.2, 0.4 or 0.6 mg/kg Fe/day the doses of 10, 20 or 30 mg/kg, respectively, are estimated to achieve iron balance (eg for a 44 kg person receiving 4 units of blood/month a dose of 30 mg/kg would be required to achieve iron balance). Further analysis reveals that chelation efficiency does appear to increase somewhat with iron intake: in patients with <0.3 mg/kg/day Fe (average 0.23) the estimated efficiency is 22%, but becomes 34% in those with >0.5 mg/kg/day Fe (average 0.55). Applying different chelation efficiency estimates for low and high iron intake, 14 and 22 mg/kg/day DSX, respectively, would be required to chelate the transfused iron. In Study 0107, 230 patients were treated with deferoxamine (DFO) at an average daily dose of 45 mg/kg (5 days/week). Using the molecular weight of DFO (656) and a factor of 1 for a hexadentate ligand in the calculation, the overall chelation efficiency for DFO is 13% (10–17% in the lowest and highest iron intake categories, respectively). These calculations, based on the formula of Angelucci et al, correspond well to the overall observation in the DSX clinical studies, that iron balance or net negative iron balance is achieved by daily doses of 20–30 mg/kg in regularly transfused patients. The results also confirm that the estimated chelation efficiency of DSX is around twice that of DFO.

A Randomized, Controlled Phase II Trial in Sickle Cell Disease Patients with Chronic Iron Overload Demonstrates That the Once-Daily Oral Iron Chelator Deferasirox (Exjade®, ICL670) Is Well Tolerated and Reduces Iron Burden.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 313-313 ◽  
Author(s):  
E. Vichinsky ◽  
R. Fischer ◽  
E. Fung ◽  
O. Onyekwere ◽  
J. Porter ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
Iron Chelator ◽  
Iron Intake ◽  
Cell Disease ◽  
Once Daily ◽  
To Receive ◽  
Iron Excretion

Abstract Repeated blood transfusion to prevent complications places patients with sickle cell disease at risk for morbidity from chronic iron overload. Parenteral chelation with deferoxamine (DFO) is effective at reducing iron overload but patient compliance is generally poor. Deferasirox (DSX) is an investigational iron chelator given orally once-daily. Demonstration of the safety and tolerability of DSX over a 1-year period was the primary objective and efficacy was a secondary objective of the study. Adult and pediatric patients (n=195; n=98 aged <16) were randomized 2:1 to receive treatment with DSX (n=132) or DFO (n=63). Dosing of DSX from 5 to 30 mg/kg/day and DFO from 20 to 60 mg/kg/day was based upon baseline liver iron concentration (LIC) as determined by liver susceptometry using a superconducting quantum interference device (SQUID). Initial DSX doses <20 mg/kg were increased midway through the trial based upon emerging data from other DSX trials. Safety assessments included hematology, chemistry, eye exams, hearing tests and ECGs. Efficacy was measured by LIC, change in serum ferritin, and iron balance. Discontinuations were similar in the DSX and DFO groups (11.4 vs 11.1%). The mean ± SD doses of DSX and DFO given were 17.3 ± 6.0 and 36.0 ± 11.4 mg/kg, and transfusional iron intake was 0.21 ± 0.13 and 0.23 ± 0.12 mg/kg/day, respectively. The most common adverse events associated with DSX were generally mild and consisted of nausea, vomiting, diarrhea, abdominal pain and skin rash. Mild non-progressive increases in serum creatinine greater than 33% of baseline and above the upper limit of normal were observed in three patients receiving DSX. One patient on DSX developed an elevated ALT most likely related to drug administration that resolved with its discontinuation. Median mg/kg/day Parameter n Mean ± SD n Mean ± SD DSX DFO DSX DFO LIC change (mg Fe/g dw) 113 −1.3 ± 3.1 54 −0.7 ± 2.6 16.7 32.7 Ferritin change (μg/L) 83 −183 ± 1651 33 −558 ± 951 Ratio iron excretion/intake 105 1.14 ± 0.60 52 1.20 ± 0.78 With both DSX and DFO there was a statistically significant reduction in LIC from baseline (P<0.0001 for DSX, P=0.022 for DFO). Efficacy of DSX and DFO was similar after 1 year of therapy. A dose-effect relationship was observed: patients assigned to receive DSX 30 mg/kg and DFO ≥ 50 mg/kg had an absolute change in serum ferritin of −1196 ± 2674 (n=10) and −936 ± 1115 μ g/L (n=7), respectively. Although serum ferritin varied during the trial with both treatments, the reduction at end of study was consistent with the effect on LIC. The ratio of iron excretion to iron intake of >1 also indicates that DSX was able to induce negative body iron balance. Once-daily oral DSX is well tolerated and appears to have similar efficacy to DFO in reducing iron burden in transfused patients with sickle cell disease.

Sustained Protection from Labile Plasma Iron (LPI) with the Once-Daily, Oral Iron Chelator Deferasirox (Exjade®, ICL670) in Iron-Overloaded β-Thalassemia Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1773-1773 ◽  
Author(s):  
S. Daar ◽  
A. Taher ◽  
A. Pathare ◽  
H. Nick ◽  
U. Krahn ◽  
...  
Keyword(s):  
Iron Concentration ◽  
Iron Chelator ◽  
Post Dose ◽  
Liver Iron ◽  
Once Daily ◽  
Excess Iron ◽  
Normal Limits ◽  
Cellular Iron ◽  
Clinically Significant ◽  
Iron Pool

Abstract Excess iron leads to the appearance of NTBI in the blood, which has been hypothesized to increase the risk for developing co-morbidities. LPI, one form of NTBI, is redox-active and can produce harmful reactive oxygen species. LPI is readily taken up by cells, resulting in expansion of the cellular iron pool. As LPI is produced 24 hours per day, the constant presence of an iron chelator in the plasma may help avoid accumulation of excess iron. Due to its long t½, clinically significant levels of deferasirox are present in the plasma for 24 hours following once-daily administration. This 1-year substudy has evaluated whether deferasirox treatment produced a sustained reduction in LPI. LPI, liver iron concentration (LIC; by biopsy) and serum ferritin (SF) levels over 1 year of treatment with deferasirox 20–30 mg/kg/day have been analyzed in a subgroup of 14 β-thalassemia patients from the ESCALATOR trial, all of whom had previously received DFO/deferiprone combination therapy. Blood samples for LPI and PK assessments were taken pre dose (predicted LPI daily peak) and 2 hours post dose (predicted daily LPI nadir), at baseline and following repeat dosing at weeks 4, 16, 28, 40 and 52. Efficacy and safety were assessed monthly, primarily by evaluating SF and the incidence and type of adverse events (AEs). LIC was measured at baseline and study end. The subgroup comprised 6 males and 8 females with a mean age of 17.5 years (range 12–27). Mean baseline iron parameters were: LPI 0.99 ± 0.82 μmol/L, LIC 28.6 ± 10.3 mg Fe/g dw, SF 7122 ± 3282 ng/mL. Baseline LPI levels were well correlated with LIC (R=0.66). Median deferasirox dose was 27.5 mg/kg/day. Mean steady-state deferasirox trough plasma levels at week 4 were 22.4 ± 18.5 μM (pre dose). Significant LPI reductions were observed post versus pre dose at baseline and week 4 (P<0.0001 and P=0.0077, respectively; Table). Pre dose LPI levels were close to normal (0–0.4 μmol/L) by week 4, and within the normal range by week 16 and thereafter throughout the study. LPI, pre and post deferasirox dose (corresponding to nadir and Cmax, respectively), at baseline and after repeat doses* LPI, μmol/L Week Mean ± SD Baseline vs repeat pre *As 1 pt died between wks 4–16, LPI data are taken from 13 pts, except †n=11 and ‡n=12 due to lost samples Baseline Pre 0.99 ± 0.82 Post 0.12 ± 0.16 4 Pre 0.45 ± 0.58 P=0.0735 Post 0.08 ± 0.20 16 Pre 0.21 ± 0.27 P=0.0015 Post 0.02 ± 0.06 28 Pre 0.15 ± 0.18 P=0.0006 Post 0.04 ± 0.05 40† Pre 0.11 ± 0.15 P=0.0007 Post 0.30 ± 0.36 52‡ Pre 0.27 ± 0.74 P=0.0070 Post 0.08 ± 0.21 During the study, LIC decreased by 6.8 ± 6.2 mg Fe/g dw, while SF decreased by 752 ± 1500 ng/mL. Deferasirox treatment was well tolerated, with no discontinuations due to AEs. The most common AEs were mild nausea (n=4) and vomiting (n=3). Conclusions: Despite a high baseline iron burden in these patients, these results highlight the ability of once-daily deferasirox 20–30 mg/kg/day to reduce levels of toxic LPI and maintain them within normal limits. Deferasirox daily trough levels were within the therapeutic range, demonstrating constant 24-hour chelation coverage. Decreases in LPI were accompanied by decreases in mean LIC and SF, indicating effective iron removal by deferasirox.

Deferasirox (Exjade®, ICL670) Demonstrates Dose-Related Effects on Body Iron Levels Related to Transfusional Iron Intake in Transfusion-Dependent Anemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2694-2694 ◽  
Author(s):  
P. Greenberg ◽  
G. Dine ◽  
A. Ganser ◽  
G. Verhoef ◽  
L. DeBusscher ◽  
...  
Keyword(s):  
Serum Ferritin ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Intake Rate ◽  
Iron Intake ◽  
Absolute Change ◽  
Body Iron ◽  
Transfusion Requirements ◽  
Iron Excretion ◽  
Intake Ratio

Abstract Iron overload, a potentially serious consequence of multiple blood transfusions, can be effectively managed with chelation therapy. Deferasirox, an investigational once-daily oral chelator, has been evaluated in a 1 year study of iron-overloaded adult and pediatric patients (n=184) with transfusion-dependent anemia including β-thalassemia, myelodysplastic syndromes (MDS) and Diamond-Blackfan anemia (DBA). Patients were stratified into four daily dose groups (5, 10, 20 and 30 mg/kg) according to baseline liver iron concentration (LIC; 2–3, &gt;3–7, &gt;7–14 and &gt;14 mg Fe/g dw, respectively). Iron balance was determined for all patients, based on transfusional iron intake and chelator-induced iron excretion, derived from the change in LIC during the study (Table 1). Patient characteristics, LIC, serum ferritin and iron excretion/intake ratio during deferasirox treatment β-thalassemia (n=85) DBA (n=30) MDS (n=47) Other anemias (n=22) *Mean ± SD Age*, years 24.7 ± 10.0 16.1 ± 10.3 65.1 ± 12.5 35.8 ± 22.9 Body weight, kg 51.1 ± 14.1 39.1 ± 18.7 70.4 ± 12.5 56.1 ± 18.5 Deferasirox dose*, mg/kg 23.8 ± 7.2 23.6 ± 7.4 20.0 ± 8.3 21.9 ± 6.5 Iron intake*, mg/kg/day 0.35 ± 0.12 0.40 ± 0.11 0.28 ± 0.14 0.31 ± 0.19     &lt;0.3, n (%) 28 (33) 6 (20) 25 (53) 10 (45)     0.3–0.5, n (%) 49 (58) 19 (63) 20 (43) 7 (32)     &gt;0.5, n (%) 8 (9) 5 (17) 2 (4) 5 (23) Serum ferritin*, ng/mL     Baseline 4321 ± 2881 3245 ± 2439 3343 ± 1978 3144 ± 1850     Absolute change −386 ± 1626 −118 ± 1373 −268 ± 2053 −750 ± 1517 LIC*, mg Fe/g dw (n=76) (n=26) (n=28) (n=17)     Baseline 19.3 ± 10.9 18.8 ± 10.7 15.6 ± 11.9 15.1 ± 6.2     Absolute change −4.7 ± 8.6 −1.6 ± 6.5 −5.7 ± 6.3 −3.7 ± 6.3 Iron excretion/intake ratio 1.5 ± 0.90 1.1 ± 0.46 1.7 ± 0.93 1.6 ± 1.48 Transfusion requirements and iron intake during the study varied widely between diseases. However, LIC and serum ferritin decreases were consistently achieved in all patient groups. More than one-third (38%) of patients, most of whom had MDS or other anemias, had an iron intake rate &lt;0.3 mg/kg/day (average: 0.2 mg/kg/day; corresponding to 5.6 ml RBC/kg/month). In these patients, deferasirox at 10 and 20 mg/kg reduced LIC. Overall, an iron intake- and dose-related response pattern was observed for both LIC and serum ferritin (Figure 1). Effect of deferasirox dose and iron intake on changes in serum ferritin and LIC over 1 year Effect of deferasirox dose and iron intake on changes in serum ferritin and LIC over 1 year According to these results, deferasirox demonstrates the ability to stabilize and effectively decrease body iron levels at doses of 10, 20 and 30 mg/kg/day, depending on the degree of iron intake. In conclusion, dosing of chelation therapy should be guided by a patient’s transfusion requirements and the treatment goal, which is either to maintain or reduce body iron.

Deferasirox (Exjade®, ICL670) Treatment of Inadequately Chelated β-Thalassemia Patients from the Middle East: The ESCALATOR Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3840-3840 ◽  
Author(s):  
Ali Taher ◽  
Amal El-Beshlawy ◽  
Abdullah Al Jefri ◽  
Mohsen El Alfy ◽  
Kusai Al Zir ◽  
...  
Keyword(s):  
Iron Overload ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelator ◽  
Oral Iron ◽  
Study Cohort ◽  
Liver Iron ◽  
Transfusion Therapy ◽  
Once Daily ◽  
Oral Iron Chelator

Abstract Iron overload is a potentially life-threatening consequence of multiple blood transfusions. Effective iron chelation therapy reduces morbidity and saves lives. Many patients are unable to comply with current treatments, deferoxamine (DFO) or deferiprone (L1), because they cannot tolerate the parenteral infusion regimen required for DFO, because of adverse events (AEs), or because they do not respond to treatment. The objective of the ESCALATOR trial is to evaluate the effectiveness of deferasirox, an investigational once-daily oral iron chelator in advanced clinical development, in reducing liver iron concentration (LIC) in patients with β-thalassemia unable to be properly treated with DFO and/or L1. During a 1-year treatment period, patients will receive deferasirox at a daily dose of 20 mg/kg. Reduction of LIC is the primary endpoint, as assessed by biopsy at baseline and study end. Secondary efficacy variables include serum ferritin (SF) and other potential surrogate markers of iron overload such as concentration of labile plasma iron (LPI) in a subgroup of patients. Safety assessments include AEs and comprehensive laboratory evaluations. To date, 232 patients have initiated treatment at seven centers in five countries (Egypt, Saudi Arabia, Lebanon, Oman, Syria). Demographics, relevant medical history and baseline iron burden parameters are described in the table. Importantly, baseline SF values were significantly correlated with LIC (R=0.63; P&lt;0.0001). The last patient’s last visit will be in June 2006. Age 2 to &lt;16 years (n=159) Age ≥16 years (n=73) All patients (n=232) Mean ± SD; †n=14 Female:male, n 79:80 35:38 114:118 Race (caucasian:oriental:other), n 59:81:19 11:41:21 70:122:40 BMI*, kg/m2 17.4 ± 2.6 21.6 ± 3.2 18.7 ± 3.4 Weight*, kg 29.4 ± 9.9 54.7 ± 9.7 37.3 ± 15.3 Hepatitis B or C, n 43 29 72 Splenectomy, n 46 53 99 Transfusions in previous year*, n 15.5 ± 4.5 14.3 ± 3.7 15.1 ± 4.3 Total volume transfused in previous year*, mL 5265 ± 2469 7446 ± 2953 5873 ± 2784 Years on chelation therapy*, n 6.2 ± 3.5 12.7 ± 4.8 8.2 ± 4.9 Proportion of life on transfusion therapy*, % 89.3 ± 13.9 89.0 ± 14.1 89.2 ± 14.0 Liver pathology grading (modified HAI scale)     Grade 0–6 143 64 207     Grade 7–12 4 0 4     Grade 13–18 0 0 0 LIC, mg Fe/g dw     Mean ± SD 17.1 ± 8.5 20.0 ± 10.0 18.0 ± 9.1     Median (min, max) 16.6 (2.9, 38.2) 19.0 (2.9, 48.9) 17.5 (2.9, 48.9) SF, ng/mL     Mean ± SD 3957 ± 2342 4564 ± 4117 4148 ± 3019     Median (min, max) 3356 (914, 13539) 3335 (956, 23017) 3346 (914, 23017) LPI†,μmol/L     Mean ± SD - - 1.03 ± 0.80     Median (min, max) - - 0.82 (0, 2.65) The ESCALATOR study cohort is a highly challenging population with varied chelation response and transfusion history. The magnitude of LIC and SF, which were well correlated, reflects the severity of iron overload in patients unable to maintain adequate chelation using DFO or L1. This study will provide important insights into the clinical management of iron overload with the well tolerated, once-daily oral iron chelator deferasirox in this difficult-to-treat population.

Efficacy and Safety of Once-Daily, Oral Iron Chelator Deferasirox (Exjade®) in a Large Group of Regularly Transfused Patients with β-Thalassemia Major

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3878-3878 ◽  
Author(s):  
Maria Domenica Cappellini ◽  
Mohsen Saleh Elalfy ◽  
Antonis Kattamis ◽  
John F Seymour ◽  
Chan Lee Lee ◽  
...  
Keyword(s):  
Iron Concentration ◽  
Chelating Agent ◽  
Thalassemia Major ◽  
P Value ◽  
Efficacy And Safety ◽  
Iron Intake ◽  
Liver Iron ◽  
Once Daily ◽  
Transfusion Requirements ◽  
Median Change

Abstract Background: The 1-year, prospective, multicenter EPIC trial, the largest ever conducted for an iron-chelating agent, evaluated the efficacy and safety of the once-daily, oral chelator deferasirox (Exjade®) in patients (pts) with transfusion-dependent anemias. 54% of 1744 pts had β-thalassemia major, providing one of the largest data sets assessing the use of deferasirox in this group. Data from this subgroup are presented. Methods: Pts (≥2 years old) with transfusional iron overload due to β-thalassemia and serum ferritin (SF) levels of ≥1000 ng/mL or <1000 ng/mL but with a history of multiple transfusions (>20 transfusions or 100 mL/kg of blood) and R2 MRI-confirmed liver iron concentration >2 mg Fe/g dry weight, received an initial deferasirox dose of 10–30 mg/kg/day dependent on transfusion requirements. Protocol-specified dose adjustments in steps of 5–10 mg/kg/day (range 0–40 mg/kg/day) were done every 3 months based on SF trends and safety markers. The change at week 52 from baseline (BL) was the primary efficacy endpoint. Results: 937 pts with β-thalassemia major, 450 males and 487 females (mean age 18.4±10.8 years), were enrolled. Median BL SF was 3157 ng/mL (range 462–22320). In the year prior to enrollment, pts received a mean of 189.8 mL/kg of blood (range 0–1768). Most pts (n=625; 66.7%) had received deferoxamine (DFO); 234 (25.0%) DFO/deferiprone combination, 12 (1.3%) deferiprone alone and four (0.4%) other therapy; 66 (7.0%) were chelation naive. 798 pts (85%) started on ≤20 mg/kg/day and 139 (15%) on >20 mg/kg/day. 51% required a dose increase at a median of 24 weeks after treatment initiation (range 2–53). After 1 year, median SF significantly decreased from BL by 129 ng/mL (P=0.0007) at an average actual dose of 24.2±5.6 mg/kg/day. Pts receiving an average actual dose of ≥30 mg/kg/day achieved a significant reduction in SF at 1 year. Pts receiving an average actual dose of <20 or ≥20–<30 mg/kg/day maintained their iron balance. SF change by mean actual dose received is shown in Table 1. The magnitude of reduction in SF was reflective of dose adjustments throughout the study. Table 1. Median change from BL in SF (ng/mL) by average actual dose received BL End of study Average actual dose categories Mean iron intake, mg/kg/day n Median SF n Median change from BL in SF P -value versus BL <20 mg/kg/day 0.38 193 2318 187 −14 0.67 ≥20–<30 mg/kg/day 0.46 614 3108 611 −45 0.56 ≥30 mg/kg/day 0.35 130 5154 130 −962 <0.0001 All pts 0.43 937 3157 928 −129 0.0007 Only 9.5% of pts (n=89) discontinued therapy. Reasons for withdrawal were AEs (n=31, 3.3%), consent withdrawal (n=24, 2.6%), unsatisfactory therapeutic effect (n=12, 1.3%), lost to follow-up (n=5, 0.5%), death (n=4, 0.4%, three due to cardiac failure and one to septicemia following surgery, none treatment related by investigators’ assessment) and other (n=13, 1.4%). The most common investigator-assessed drug-related AEs were rash (n=115, 12.3%), diarrhea (n=76, 8.1%) and abdominal pain (n=50, 5.3%). The majority of AEs were mild-to-moderate (>95%). Thirty-seven pts (3.9%) had serum creatinine >33% above BL and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. Five (0.5%) pts had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in four pts. Conclusions: These data confirm that in heavily iron-loaded pts with β-thalassemia major, higher deferasirox doses are needed to achieve significant reductions in SF, while lower doses are able to maintain iron balance. The starting dose guided by the rate of iron intake from blood transfusions and current iron burden should be titrated individually and promptly (at 3 months) according to SF trends and safety markers. Deferasirox treatment in this subgroup was generally well tolerated (including doses ≥30 mg/kg/day) with a low discontinuation rate.

Iron Chelation Therapy with Deferasirox (Exjade®, ICL670) or Deferoxamine Is Effective in Reducing Iron Overload in Patients with Advanced Fibrosis and Cirrhosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2696-2696 ◽  
Author(s):  
E. Angelucci ◽  
B. Turlin ◽  
D. Canatan ◽  
A. Mangiagli ◽  
V. De Sanctis ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Iron Chelator ◽  
Advanced Fibrosis ◽  
Liver Iron ◽  
Once Daily ◽  
Tissue Iron

Abstract Introduction: Although the direct measurement of iron from a liver biopsy is the reference standard method to determine liver iron concentration (LIC), results are highly unreliable in patients with advanced fibrosis and cirrhosis. As a result, chelation therapy is difficult to monitor in this patient population where effective chelation therapy may be critical. It is therefore important to assess parameters additional to LIC in order to accurately assess body iron in these patients. Aim: To analyze the efficacy of chelation with deferoxamine (DFO) and the investigational once-daily, oral iron chelator deferasirox (DSX) in patients with advanced fibrosis participating in DSX registration studies. Methods: A subgroup of patients from DSX Studies 0107 and 0108 were selected based on a staging result according to the Ischak scale of 5 (incomplete cirrhosis) or 6 (probable or definite cirrhosis), measured either at baseline or after 1 year of chelation therapy. The subgroup of patients with β-thalassemia participating in Study 0107 received DSX (n=26) or DFO (n=30). In Study 0108, the subgroup of patients with β-thalassemia unable to be treated with DFO (n=12) or patients with anemias other than β-thalassemia (n=7) were treated with DSX only. In both studies, patients received chelation therapy according to baseline LIC. Results: In Study 0107, treatment with DSX or DFO led to a decrease in semi-quantitative tissue iron score (TIS) and LIC, which were paralleled by changes in serum ferritin. TIS, LIC and serum ferritin in a subgroup of patients with advanced fibrosis and cirrhosis treated with DSX and DFO (Study 0107) TIS LIC, mg Fe/g dw Serum ferritin, ng/mL DSX (n=26) DFO (n=30) DSX (n=26) DFO (n=30) DSX (n=26) DFO (n=30) *Median (min, max) Baseline* 35.5 (4,39) 34 (10,52) 25.5 (2.4,45.9) 19.5 (3.9,55.1) 4195 (321,12646) 4144 (653,15283) Change from baseline* −2 (−43,20) −2 (−25,16) −9.4 (−42.2,13.1) −3.1 (−24.5,12.4) −1269 (−7082,3609) −951 (−8259,1264 Similarly, in Study 0108, DSX treatment produced a decrease in all 3 parameters in patients with β-thalassemia or rare anemia. TIS, LIC and serum ferritin in a subgroup of β-thalassemia and rare anemia patients with advanced fibrosis and cirrhosis (Study 0108) TIS LIC, mg Fe/g dw Serum ferritin, ng/mL β-thalassemia (n=12) Rare anemia (n=7) β-thalassemia (n=12) Rare anemia (n=7) -thalassemia β (n=12) Rare anemia (n=7) *Median (min, max) Baseline* 35 (4,48) 41 (32,49) 29.4 (3.8,37.4) 26.3 (15,51.3) 4813 (440,11698) 2385 (1553,9099) Change from baseline* 2 (−19,27) −3 (−20,1) −1.6 (−18,9.9) −10 (−13.9,8.8) −986 (−4453,2131) −1322 (−2609,1901) Conclusions: Chelation therapy with DSX or DFO is effective in reducing iron overload in patients with advanced fibrosis and cirrhosis. The trends observed in TIS and LIC were closely mirrored by changes in serum ferritin, highlighting the validity of this method for monitoring chelation therapy in this population.

Impact on Iron Removal of Dose Reduction for Non-Progressive Serum Creatinine Increases during Treatment with the Once-Daily, Oral Iron Chelator Deferasirox (Exjade®, ICL670).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3824-3824 ◽  
Author(s):  
N. Gattermann ◽  
N. Zoumbos ◽  
E. Angelucci ◽  
G. Drelichman ◽  
J. Siegel ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Dose Reduction ◽  
Iron Concentration ◽  
Development Program ◽  
Iron Removal ◽  
Iron Intake ◽  
Liver Iron ◽  
Elevated Creatinine ◽  
The Impact ◽  
Iron Excretion

Abstract Introduction: During the deferasirox clinical development program, mild, non-progressive increases in serum creatinine >33% above baseline were observed in around one-third of patients receiving the chelator. Most increases resolved spontaneously, while the rest were managed by dose reduction. This post-hoc analysis evaluates the impact on efficacy of reducing deferasirox dose following increases in serum creatinine during 1-year core trials. Methods: Patients with a range of transfusion-dependent anemias, including β-thalassemia, sickle cell disease, myelodysplastic syndromes and other anemias, were enrolled into four trials. Creatinine and creatinine clearance levels were assessed monthly, and liver iron concentration (LIC) was measured at baseline and study end. Results: In total, 652 patients received treatment with deferasirox. Non-progressive creatinine increases >33% above baseline were noted in 237 (36.3%) patients, although these increases rarely exceeded the upper limit of normal (4.4%). These non-progressive increases generally occurred early, were dose- and iron intake-dependent, and were consistent across all ages and underlying anemias. Creatinine levels spontaneously reduced in 169 patients (71.3%); the remainder (n=68, 28.7%) underwent dose reduction by 5–10 mg/kg/day. Patients receiving high versus low doses and with low (<7 mL RBC/kg/month) versus high (>14 mL RBC/kg/month) transfusion rates tended to have the greatest and most rapid reductions in LIC. This greater velocity of iron removal tended to result in elevated creatinine levels. Patients with elevated creatinine who required dose reduction actually had more pronounced reductions in LIC than patients with no creatinine increase or with a creatinine increase that did not require dose reduction (Table). Change from baseline in LIC (mg Fe/g dw) by creatinine levels Initial dose, mg/kg/day No creatinine increase (n=415) Creatinine increase (n=237) No dose reduction (n=169) Dose reduction (n=68) All Iron intake, mg/kg/day 0.35 ± 0.15 0.34 ± 0.13 0.30 ± 0.11 All Median 0.4 −3.2 −6.9 Range (−24.9–15.0) (−42.2–10.8) (−21.6–5.0) 5 Median 4.9 2.1 0.8 Range (−1.0–11.4) (2.1) (0.8) 10 Median 1.3 0.2 −1.0 Range (−11.8–15.0) (−7.3–10.8) (−2.1–3.6) 20 Median 0.0 −1.9 −3.9 Range (−9.4–10.3) (−10.3–6.5) (−10.6–1.1) 30 Median −5.7 −9.9 −9.3 Range (−24.9–13.3) (−42.2–8.6) (−21.6–5.0) Non-progressive increases in creatinine were more commonly observed in patients with an iron excretion/intake ratio >1.5 (14%) than in those with a ratio 1−1.5 (11%) or <1 (9%). Conclusions: An early-onset, non-progressive, dose- and iron intake-dependent increase in creatinine has been observed in around one-third of patients receiving deferasirox. Most of these increases resolved spontaneously, while the rest were manageable with dose reduction. As decreases in LIC were generally greatest in patients with increased creatinine levels, supported by the iron excretion/intake ratios, it is hypothesized that excessively rapid iron removal may modify renal hemodynamics. A reduction in deferasirox dose maintained efficacy, but allowed the dose to be tailored so that iron was removed at a rate appropriate for an individual patient.

Optimizing Iron Chelator Treatment in Cardiac and Hepatic Siderosis: Efficacy of Divided Deferasirox (EXJADER) – Doses

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2110-2110
Author(s):  
Regine Grosse ◽  
Andrea Jarisch ◽  
Jin Yamamura ◽  
Peter Nielsen ◽  
Roland Fischer ◽  
...  
Keyword(s):  
Iron Overload ◽  
Treatment Period ◽  
Iron Concentration ◽  
Iron Chelator ◽  
Liver Iron ◽  
Once Daily ◽  
Cardiac Iron ◽  
Cardiac Siderosis ◽  
Cardiac Iron Overload ◽  
The Mean

Abstract Abstract 2110 Introduction: Iron chelation is the life-saving therapy in patients with chronic transfusion therapy. Treatment with deferoxamine, deferiprone or deferasirox has dramatically improved the life expectancy, but still myocardial siderosis and hepatic siderosis is cause of morbidity and mortality in regularly transfused patients with ß-thalassemia major (TM) or Diamond-Blackfan Anemia (DBA). Deferasirox (DSX) a once-daily oral iron chelator has demonstrated efficacy in reducing hepatic iron and body iron burden, as well as cardiac iron. But in patients with severe cardiac siderosis (T2* ≤ 10ms) a combination therapy with deferiprone (Ferriprox®) and deferoxamine (Desferal®) is the recommended therapy. However, some patients will not benefit from this treatment due to unacceptable toxicity, poor response or noncompliance. Method: We tested a twice-daily deferasirox (Exjade®) -dose with special respect to its efficacy on reducing cardiac iron overload. A group of six patients with severe secondary siderosis was studied, TM (n=5) and DBA (n=1), (5 females, age 8–37 years, mean age 27.7 years). In all patients the liver iron concentration was measured repeatedly by SQUID biosusceptometry or by magnetic resonance imaging (MRI) using the MRI-R2 technique (St. Pierre et al, 2005). In 4 patients with severe cardiac siderosis (T2* ≤ 10ms) we also followed the cardiac iron concentration by MRI using a single breath-hold, multi-echo T2* method. Patients received a daily DSX dose of 19 mg/kg/d – 45 mg/kg/d, with a mean dose of 32 mg/kg/d. Results: The mean initial liver iron concentration of 2.7 mg/g-liver (0.96 – 5.5mg/g) decreased to 1.5 mg/g-liver (0.6 – 3.9 mg/g). The mean monthly liver iron clearance was 6.8%/month (1.7 – 16.8%/month) in a treatment interval of 4 – 26 months (mean: 9.8 months), the patients demonstrated a significant liver iron reduction of 44.4%. The mean serum ferritin was reduced from 3048 μg/l to 1786 μg/l. The mean monthly cardiac iron clearance was 3.1%/month (1.2 – 4.7%/month) and the mean T2* value improved from 9.5 ms to 14.3 ms (+50%). We showed a substantial improvement in patients with severe cardiac siderosis with a T2* improvement of 50 % after a mean treatment period of 12 months with a mean DSX dose of 32 mg/kg/d. In comparison, an improvement of 23.8% was found in 6 patients with T2* < 10 ms, after a treatment period of 18 months with a once daily DSX mean dose of 38 mg/kg/d (Pathare et al, 2010). Other authors reported an improvement of 10.8% in 47 patients (T2* < 10 ms, treatment period 12 months) with a once daily DSX mean dose of 32 mg/kg/d (Pennell et al, 2009). No severe side effects were seen in our patients and only minor increases in creatinine values, which were reversible with dose reduction. Conclusion: Deferasirox divided in twice daily doses is a safe and effective therapy for patients with severe cardiac iron overload (T2* < 10ms) or hepatic iron overload, who do not well tolerate a combination therapy with deferiprone and deferoxamine. Disclosures: Off Label Use: Deferasirox (Exade)is given instead of a once daily dose, in a twice daily divided dose. The daily dose of Deferasirox is in recommended range.

Spinal Peroxynitrite Contributes to Remifentanil-induced Postoperative Hyperalgesia via Enhancement of Divalent Metal Transporter 1 without Iron-responsive Element–mediated Iron Accumulation in Rats

2015 ◽  
Vol 122 (4) ◽  
pp. 908-920 ◽  
Author(s):  
Rui-Chen Shu ◽  
Lin-Lin Zhang ◽  
Chun-Yan Wang ◽  
Nan Li ◽  
Hai-Yun Wang ◽  
...  
Keyword(s):  
Manganese Superoxide Dismutase ◽  
Iron Concentration ◽  
Iron Chelator ◽  
Iron Accumulation ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Iron Responsive Element ◽  
Manganese Superoxide ◽  
Responsive Element

Abstract Background: Hyperalgesia is one of the negative consequences following intraoperative analgesia with remifentanil. Peroxynitrite is a critical determinant in nociceptive process. Peroxynitrite inactivates iron-sulfur cluster that results in mitochondrial dysfunction and the release of iron, leading to mitochondrial iron accumulation. Iron accumulation mediated by divalent metal transporter 1 (DMT1) plays a key role in N-methyl-d-aspartate neurotoxicity. This study aims to determine whether peroxynitrite contributes to remifentanil-induced postoperative hyperalgesia via DMT1-mediated iron accumulation. Methods: Behavior testing was performed in rat model at different time points. Three-nitrotyrosine, nitrated manganese superoxide dismutase, and DMT1 with/without iron-responsive element [DMT1(+)IRE and DMT1(-)IRE] in spinal cord were detected by Western blot and immunohistochemistry. Spinal iron concentration was measured using the Perl stain and atomic absorption spectrophotometer. Hydrogen-rich saline imparting selectivity for peroxynitrite decomposition and iron chelator was applied in mechanistic study on the roles of peroxynitrite and iron, as well as the prevention of hyperalgesia. Results: Remifentanil induced thermal and mechanical hyperalgesia at postoperative 48 h. Compared with control, there were higher levels of 3-nitrotyrosine (mean ± SD, hyperalgesia vs. control, 1.22 ± 0.18 vs. 0.25 ± 0.05, n = 4), nitrated manganese superoxide dismutase (1.01 ± 0.1 vs. 0.19 ± 0.03, n = 4), DMT1(-)IRE (1.42 ± 0.19 vs. 0.33 ± 0.06, n = 4), and iron concentration (12.87 ± 1.14 vs. 5.26 ± 0.61 μg/g, n = 6) in remifentanil-induced postoperative hyperalgesia, while DMT1(+)IRE was unaffected. Eliminating peroxynitrite with hydrogen-rich saline protected against hyperalgesia and attenuated DMT1(-)IRE overexpression and iron accumulation. Iron chelator prevented hyperalgesia in a dose-dependent manner. Conclusions: Our study identifies that spinal peroxynitrite activates DMT1(-)IRE, leading to abnormal iron accumulation in remifentanil-induced postoperative hyperalgesia, while providing the rationale for the development of molecular hydrogen and “iron-targeted” therapies.

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