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Effect of Genetic Polymorphisms on the Pharmacokinetics of Deferasirox in Healthy Chinese Subjects and an Artificial Neural Networks Model for Pharmacokinetic Prediction.
Chen, J, Xu, Y, Lou, H, Jiang, B, Shao, R, Yang, D, Hu, Y, Ruan, Z
European journal of drug metabolism and pharmacokinetics. 2020;(6):761-770
Abstract
BACKGROUND AND OBJECTIVE Deferasirox is an oral iron chelator used to reduce iron levels in iron-overloaded patients with transfusion-dependent anemia or non-transfusion-dependent thalassemia. This study investigated the effects of genetic polymorphisms on the pharmacokinetics of deferasirox in healthy Chinese subjects and constructed a pharmacokinetic prediction model based on physiologic factors and genetic polymorphism data. METHODS Twenty-eight subjects were enrolled in a randomized, open-label, two-period crossover study, and they received a single dose of one of two formulations of deferasirox (20 mg/kg) with a 7-day washout interval between the two periods. The plasma defersirox concentration was determined using a validated liquid chromatography-tandem mass spectrometry method, and pharmacokinetic parameters were calculated using the noncompartmental method. The polymorphisms of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), UGT1A3, multidrug resistance protein 2 (MRP2), cytochrome P450 1A1 (CYP1A1), and breast cancer resistance protein 1 (BCRP1) were genotyped using Sanger sequencing. A back-propagation artificial neural network (BP-ANN) model was used to predict the pharmacokinetics. RESULTS The UGT1A1 rs887829 C > T single-nucleotide polymorphism (SNP) significantly influenced the area under the plasma concentration-time curve and the terminal half-life. Neither the MRP2 rs2273697 G > A SNP nor BCRP1 rs2231142 G > T SNP altered the absorption, disposition, and excretion of the drug. The BP-ANN model had a high goodness-of-fit index and good coherence between the predicted and measured concentrations (R2 = 0.921). CONCLUSION Metabolic enzyme-related genetic polymorphisms were more strongly associated with the pharmacokinetics of deferasirox than membrane transporter-related genetic polymorphisms in the Chinese population. TRIAL REGISTRATION www.Chinadrugtrials.org.cn CTR20191164.
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Pantoprazole reduces serum ferritin in patients with thalassemia major and intermedia: A randomized, controlled study.
Eghbali, A, Khalilpour, A, Taherahmadi, H, Bagheri, B
Therapie. 2019;(5):507-512
Abstract
AIM: Complications due to iron overload exert a problematic situation in patients with thalassemia. Proton pump inhibitors (PPIs) like pantoprazole are effective agents to reduce acid gastric acid secretion and perhaps to interrupt iron absorption in conditions with increased iron absorption. Our purpose was to study effects of pantoprazole addition to chelators on iron levels in patients with thalassemia major and intermedia. METHODS This randomized, controlled, and single center trial was performed on 60 patients with thalassemia major and intermedia in Amir Kabir hospital, Iran. Patients were randomized 1:1 to pantoprazole group (iron chelator plus pantoprazole) or control group (iron chelator) for 6 months. Serum ferritin was measured by ELISA. Iron content was measured by magnetic resonance imaging; heart T2*, and liver T2*. RESULTS After 6 months of treatment, a significant reduction was seen in serum ferritin levels in the pantoprazole group (1444±613μg/mL to 1197±956μg/mL; P<0.001). A further reduction was seen in patients with thalassmeia intermedia. There were no significant changes in myocardial T2* values in pantoprazole group compared to control group (23.6±7.3ms to 24.1±6.4ms). Compared to the control group, pantoprazole therapy had no effect on hepatic T2* value (9.7±2.3ms to 9.8±2.6ms). However, between-group difference was significant (P<0.05). CONCLUSION Pantoprazole therapy for 6 months has benefits for reducing serum ferritin in patients with thalassemia major and intermedia. Pantoprazole addition to iron chelators seems safe.
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Patient-reported outcomes from a randomized phase II study of the deferasirox film-coated tablet in patients with transfusion-dependent anemias.
Taher, AT, Origa, R, Perrotta, S, Kouraklis, A, Ruffo, GB, Kattamis, A, Goh, AS, Huang, V, Zia, A, Herranz, RM, et al
Health and quality of life outcomes. 2018;(1):216
Abstract
BACKGROUND Adherence to long-term chelation therapy in transfusion-dependent patients is critical to prevent iron overload-related complications. Once-daily deferasirox dispersible tablets (DT) have proven long-term efficacy and safety in patients ≥2 years old with chronic transfusional iron overload. However, barriers to optimal adherence remain, including palatability, preparation time, and requirements for fasting state. A new film-coated tablet (FCT) formulation was developed, swallowed once daily (whole/crushed) with/without a light meal. METHODS The open-label, Phase II ECLIPSE study evaluated patient-reported outcomes (PROs) in transfusion-dependent thalassemia or lower-risk myelodysplastic syndromes patients randomized 1:1 to receive deferasirox DT or FCT over 24 weeks as a secondary outcome of the study. Three PRO questionnaires were developed to evaluate both deferasirox formulations: 1) Modified Satisfaction with Iron Chelation Therapy Questionnaire; 2) Palatability Questionnaire; 3) Gastrointestinal (GI) Symptom Diary. RESULTS One hundred seventy three patients were enrolled; 87 received the FCT and 86 the DT formulation. FCT recipients consistently reported better adherence (easier to take medication, less bothered by time to prepare medication and waiting time before eating), greater satisfaction/preference (general satisfaction and with administration of medicine), and fewer concerns (less worry about not swallowing enough medication, fewer limitations in daily activities, less concern about side effects). FCT recipients reported no taste or aftertaste and could swallow all their medicine with an acceptable amount of liquid. GI summary scores were low for both formulations. CONCLUSIONS These findings suggest a preference in favor of the deferasirox FCT formulation regardless of underlying disease or age group. Better patient satisfaction and adherence to chelation therapy may reduce iron overload-related complications. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02125877; registered April 26, 2014.
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One-year results from a prospective randomized trial comparing phlebotomy with deferasirox for the treatment of iron overload in pediatric patients with thalassemia major following curative stem cell transplantation.
Inati, A, Kahale, M, Sbeiti, N, Cappellini, MD, Taher, AT, Koussa, S, Nasr, TA, Musallam, KM, Abbas, HA, Porter, JB
Pediatric blood & cancer. 2017;(1):188-196
Abstract
BACKGROUND Iron overload is well documented in patients with β-thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre- and immediate post-HSCT transfusions. PROCEDURE This is a prospective, randomized, 1-year clinical trial that compares the efficacy and safety of the once-daily oral iron chelator deferasirox versus phlebotomy for the treatment of iron overload in children with β-thalassemia major following HSCT. RESULTS Patients (aged 12.4 years) received deferasirox (n = 12, 10 mg/kg/day starting dose) or phlebotomy (n = 14, 6 ml/kg/2 weeks) for 1 year. In two and five patients, deferasirox dose was increased to 15 and 20 mg/kg/day, respectively. Magnetic resonance imaging (MRI)-assessed liver iron concentration (LIC) decreased with deferasirox (mean 12.5 ± 10.1 to 8.5 ± 9.3 mg Fe/g dry weight [dw]; P = 0.0005 vs. baseline) and phlebotomy (10.2 ± 6.8 to 8.3 ± 9.2 mg Fe/g dw; P = 0.05). LIC reductions were greater with deferasirox than with phlebotomy for patients with baseline serum ferritin 1,000 ng/ml or higher (-8.1 ± 1.5 vs. -3.5 ± 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and non-transferrin-bound iron also decreased significantly. In two patients with severe cardiac siderosis, a clinically relevant improvement in myocardial T2* was seen, following phlebotomy and deferasirox therapy (n = 1 each). Adverse effects with deferasirox were skin rash, gastrointestinal upset, and increased liver function tests (all n = 1), while those for phlebotomy were difficulty with venous access (n = 4) and distress during procedure (n = 1). Parents of 13/14 children receiving phlebotomy wished to switch to deferasirox, with 1/14 being satisfied with phlebotomy. CONCLUSIONS Deferasirox treatment or phlebotomy reduces iron burden in pediatric patients with β- thalassemia major post-HSCT, with a manageable safety profile.
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Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson's disease.
Martin-Bastida, A, Ward, RJ, Newbould, R, Piccini, P, Sharp, D, Kabba, C, Patel, MC, Spino, M, Connelly, J, Tricta, F, et al
Scientific reports. 2017;(1):1398
Abstract
Parkinson's disease (PD) is associated with increased iron levels in the substantia nigra (SNc). This study evaluated whether the iron chelator, deferiprone, is well tolerated, able to chelate iron from various brain regions and improve PD symptomology. In a randomised double-blind, placebo controlled trial, 22 early onset PD patients, were administered deferiprone, 10 or 15 mg/kg BID or placebo, for 6 months. Patients were evaluated for PD severity, cognitive function, depression rating and quality of life. Iron concentrations were assessed in the substantia nigra (SNc), dentate and caudate nucleus, red nucleus, putamen and globus pallidus by T2* MRI at baseline and after 3 and 6 months of treatment. Deferiprone therapy was well tolerated and was associated with a reduced dentate and caudate nucleus iron content compared to placebo. Reductions in iron content of the SNc occurred in only 3 patients, with no changes being detected in the putamen or globus pallidus. Although 30 mg/kg deferiprone treated patients showed a trend for improvement in motor-UPDRS scores and quality of life, this did not reach significance. Cognitive function and mood were not adversely affected by deferiprone therapy. Such data supports more extensive clinical trials into the potential benefits of iron chelation in PD.
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A randomized, controlled study evaluating effects of amlodipine addition to chelators to reduce iron loading in patients with thalassemia major.
Eghbali, A, Kazemi, H, Taherahmadi, H, Ghandi, Y, Rafiei, M, Bagheri, B
European journal of haematology. 2017;(6):577-581
Abstract
AIM: Cardiomyopathy due to iron overload can be fatal in patients with thalassemia major. Calcium channel blockers seem to be effective to reduce iron loading. Our goal was to study effects of amlodipine addition to chelators on iron loading in patients with thalassemia major. METHODS This randomized, controlled, and single-center trial was performed on 56 patients with thalassemia major. Patients were randomized 1:1 to combined group (iron chelator plus amlodipine) or control group (iron chelator) for 1 year. Iron content was measured by magnetic resonance imaging; heart T2*, and liver T2*. Serum ferritin was also measured. RESULTS After 12 months of treatment, myocardial T2* values had significant improvement in combined group (21.9 ± 8.0 ms to 24.5 ± 7.6 ms; P < .05); Difference between two groups was significant (P = .02). Combined treatment had no effect on hepatic T2* value (9.6 ± 2.8 ms to 9.5 ± 3.6 ms); difference between two groups was not significant (P = .2). In addition, a significant reduction was seen in serum ferritin levels in two groups. Mild gastrointestinal upset was the most common untoward effect. CONCLUSION Addition of amlodipine to iron chelators has beneficial effects for reduction of iron loading in patients with thalassemia major. This combination therapy seems safe.
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Chromium Supplementation and the Effects on Metabolic Status in Women with Polycystic Ovary Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial.
Jamilian, M, Asemi, Z
Annals of nutrition & metabolism. 2015;(1):42-8
Abstract
BACKGROUND The aim of the present study was to evaluate the beneficial effects of chromium intake on markers of insulin metabolism and lipid profiles in women with polycystic ovary syndrome (PCOS). METHODS In a prospective, randomized, double-blind, placebo-controlled trial, 64 women with PCOS were randomized to receive 200 µg chromium picolinate supplements (n = 32) or placebo (n = 32) for 8 weeks. Fasting blood samples were obtained at baseline and 8 weeks after the intervention to quantify markers of insulin metabolism and lipid concentrations. RESULTS Chromium supplementation in women with PCOS resulted in significant decreases in serum insulin levels (-3.6 ± 7.4 vs. +3.6 ± 6.2 µIU/ml, p < 0.001), homeostasis model of assessment-insulin resistance (HOMA-IR; -0.8 ± 1.6 vs. +0.9 ± 1.5, p < 0.001), homeostatic model assessment-beta cell function (HOMA-B; -15.5 ± 32.3 vs. +13.6 ± 23.1, p < 0.001), and a significant increase in quantitative insulin sensitivity check index (QUICKI) score (+0.02 ± 0.03 vs. -0.008 ± 0.02, p = 0.001) compared with the placebo. In addition, a trend toward a significant effect of chromium supplementation on decreasing serum triglycerides (-12.4 ± 74.4 vs. +15.2 ± 32.4 mg/dl, p = 0.05), very low-density lipoprotein-cholesterol (-2.5 ± 14.9 vs. +3.0 ± 6.5 mg/dl, p = 0.05), and cholesterol concentrations (-8.6 ± 21.9 vs. +0.7 ± 22.4 mg/dl, p = 0.09) was seen. CONCLUSIONS Eight weeks of chromium supplementation among PCOS women had favorable effects on markers of insulin metabolism.
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Defining serum ferritin thresholds to predict clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is unavailable in patients with non-transfusion-dependent thalassaemia.
Taher, AT, Porter, JB, Viprakasit, V, Kattamis, A, Chuncharunee, S, Sutcharitchan, P, Siritanaratkul, N, Origa, R, Karakas, Z, Habr, D, et al
British journal of haematology. 2015;(2):284-90
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Abstract
Liver iron concentration (LIC) assessment by magnetic resonance imaging (MRI) remains the gold standard to diagnose iron overload and guide iron chelation therapy in patients with non-transfusion-dependent thalassaemia (NTDT). However, limited access to MRI technology and expertise worldwide makes it practical to also use serum ferritin assessments. The THALASSA (assessment of Exjade(®) in non-transfusion-dependent THALASSemiA patients) study assessed the efficacy and safety of deferasirox in iron-overloaded NTDT patients and provided a large data set to allow exploration of the relationship between LIC and serum ferritin. Using data from screened patients and those treated with deferasirox for up to 2 years, we identified clinically relevant serum ferritin thresholds (for when MRI is unavailable) for the initiation of chelation therapy (>800 μg/l), as well as thresholds to guide chelator dose interruption (<300 μg/l) and dose escalation (>2000 μg/l). (clinicaltrials.gov identifier: NCT00873041).
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Ceruloplasmin activity and iron chelation treatment of patients with Parkinson's disease.
Grolez, G, Moreau, C, Sablonnière, B, Garçon, G, Devedjian, JC, Meguig, S, Gelé, P, Delmaire, C, Bordet, R, Defebvre, L, et al
BMC neurology. 2015;:74
Abstract
BACKGROUND Growing body of evidence suggests that Parkinson's disease (PD) is associated with oxidative damage via iron accumulation in the substantia nigra (SN). Low ceruloplasmin (CP)-ferroxidase activity has been identified in the SN and the cerebrospinal fluid (CSF) of patients with PD. The iron chelator, deferiprone, reduces the abnormally high levels of iron in the SN. In order to determine CP's involvement in iron accumulation in SN and PD progression, we aim to compare the ability of iron chelation treatment to reducing both SN iron levels and motor handicap in PD patients according to the level of ceruloplasmin activity. METHODS We used a moderate chelation protocol with deferiprone (DFP) based on a, 6-month delayed-start paradigm, randomized placebo controlled clinical trial in 40 PD patients. CP-ferroxidase activity was determined in blood and CSF together with the D544E gene polymorphism (rs701753). Iron levels were determined by R2* MRI sequence and the motor handicap by the UPDRS motor score. RESULTS After 6 to 12 months of DFP treatment, greater reductions in SN iron levels and UPDRS motor scores were obtained in patients with higher serum and CSF levels of CP-ferroxidase activity. After 6 months of DFP treatment, the AT genotype group displayed greater reduction of iron level in the SN with greater CSF and serum levels of CP activity than the AA genotype group. CONCLUSION Although most of the DFP-treated patients displayed clinical and radiological improvements, those with the lower CP activity appeared to respond better to iron chelation. Larger RCTs are now needed to establish whether pharmacological modulation of CP activity could be an innovative neuroprotective strategy in PD. TRIAL REGISTRATION FAIR-PARK study (ClinicalTrials.gov reference: NCT00943748 ; French national reference number: 2008-006842-25). This study was approved by the French Drug Agency (ANSM) and the local institutional review board ("Comité de Protection des Personnes of Lille").
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R2 and R2* are equally effective in evaluating chronic response to iron chelation.
Wood, JC, Zhang, P, Rienhoff, H, Abi-Saab, W, Neufeld, E
American journal of hematology. 2014;(5):505-8
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MRI relaxometry (R2, R2*) has generally replaced liver biopsy for estimation of liver iron stores in response to iron chelation, but there have been no longitudinal studies comparing R2 and R2* techniques. We use R2 and R2* liver iron concentration (LIC) estimates, transfusional iron burdens, and drug compliance data to calculate iron chelation efficiency (ICE) in patients undergoing a Phase II trial of SPD602. Fifty-one patients underwent a baseline examination, 39 patients completed 1 year, and 26 patients completed 2 years. Baseline LICR2 and LICR2* estimates were unbiased, but had limits of agreement exceeding 50%, suggesting that these techniques cannot be interchanged with one another in the same patient. However, ICE estimates across the two techniques compared more favorably, with r(2) values reaching 0.89 at 2 years. 95 confidence intervals for efficiency estimates were 0.0 ± 4.1%. These data indicate that clinical trial and clinical effectiveness data calculated using LICR2 and LICR2* estimates can be compared to one another, even though LIC estimates may be disparate on cross-sectional analysis. While the choice of MRI assessment technique for clinical trials and for clinical management depends on many logistical considerations, one can have confidence comparing conclusions on clinical effectiveness.