Pharmacokinetics and safety of deferasirox in subjects with chronic kidney disease undergoing haemodialysis

Siva, Brian; Batty, Kevin T.; Trengove, Robert D.; Ferrari, Paolo; Olynyk, John K.

doi:10.1111/nep.12035

Cited by 17 publications

(22 citation statements)

References 28 publications

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“…Sánchez-González et al 34 provided high dose of DFX intraperitoneally in normal rats for 1 week, whereas we gave CKD rats three doses of DFX in chow for 3 weeks and moderate dose of DFX in chow for 8 weeks. Since they evaluated renal toxicological effects of DFX in normal rats, the dose of DFX in their experiments (75 mg kg − 1 day − 1 ) was higher Iron and renal fibrosis Y Naito et al than the current experiments (15,30 and 60 mg kg − 1 day − 1 ) and the usual doses in patients (20 mg kg − 1 day − 1 ). Taken together, these results could provide a careful assessment on the excess dose of DFX.…”

Section: Discussionmentioning

confidence: 90%

Association between renal iron accumulation and renal interstitial fibrosis in a rat model of chronic kidney disease

et al. 2015

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Iron accumulation is associated with the pathophysiology of chronic kidney disease (CKD). Renal fibrosis is a final common feature that contributes to the progression of CKD; however, little is known about the association between renal iron accumulation and renal interstitial fibrosis in CKD. Here we investigate the effects of iron chelation on renal interstitial fibrosis in a rat model of CKD. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. At 8 weeks after operation, 5/6 nephrectomized rats were administered an oral iron chelator, deferasirox (DFX), in chow for 8 weeks. Other CKD rats were given a normal diet. Sham-operative rats given a normal diet served as a control. CKD rats exhibited hypertension, glomerulosclerosis and renal interstitial fibrosis. Iron chelation with DFX did not change hypertension and glomerulosclerosis; however, renal interstitial fibrosis was attenuated in CKD rats. Consistent with these findings, renal gene expression of collagen type III and transforming growth factor-β was increased in CKD rats compared with the controls, while iron chelation suppressed these increments. In addition, a decrease in vimentin along an increase in E-cadherin in renal gene expression was observed in CKD rats with iron chelation. CKD rats also showed increased CD68-positive cells in the kidney, whereas its increase was attenuated by iron deprivation. Similarly, increased renal gene expression of CD68, tumor necrosis factor-α and monocyte chemoattractant protein-1 was suppressed in CKD rats with iron chelation. Renal iron accumulation seems to be associated with renal interstitial fibrosis in a rat model of CKD.

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Section: Discussionmentioning

confidence: 90%

Association between renal iron accumulation and renal interstitial fibrosis in a rat model of chronic kidney disease

et al. 2015

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“…While no studies have been performed regarding dialytic clearance, the deferasirox binds albumin with 98–99% efficiency, likely making it poorly dialyzable . Data regarding clinical outcomes of dialysis patients using deferasirox for iron overload are confined to a few case reports.…”

Section: Anemia Management In the Esrd Population With Sickle Cell DImentioning

confidence: 75%

“…The 10 mg/kg dose did not reach the therapeutic plasma concentration whereas the 15 mg/kg dose was well beyond therapeutic range. As this drug is minimally excreted in the urine, the uremic state might confer some resistance to intestinal secretion, thus resulting in elevated plasma concentration .…”

Section: Anemia Management In the Esrd Population With Sickle Cell DImentioning

confidence: 99%

Management of the Dialysis Patient with Sickle Cell Disease

Boyle

Jacobs

Sayani

et al. 2015

Seminars in Dialysis

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While patients with sickle cell disease currently constitute a very small minority of the US dialysis population (0.1%), there is anticipated growth of this group as the life expectancy of those with sickle cell disease (SCD) increases. SCD patients suffer a high burden of morbidity, which is enhanced by the presence of end-stage renal disease (ESRD). In this review, we discuss the pathophysiology of SCD and the basic tenets of its management with focus on the dialysis patient with SCD. Anemia in dialysis patients with SCD is a unique challenge. The hemoglobin target in SCD dialysis patients with ESRD should not exceed 10 g/dl. SCD patients, and particularly those on dialysis, are likely to be poorly responsive to erythropoietin-stimulating agent (ESA) therapy and might be at increased risk for vaso-occlusive crisis (VOC) with ESA. Iron chelation and hydroyxurea therapy require special considerations and modifications in dialysis patients with SCD. There are theoretical advantages to both hemodialysis (HD) and peritoneal dialysis (PD) in SCD patients. With HD, there is a secure vascular access available for both standard and exchange blood transfusion in patients who need them. With PD, the absence of an acute rise in hematocrit with ultrafiltration (UF) might offer lower risk of VOC. During VOC, reduction in UF goals should be considered but administration of intravenous fluids should be reserved only for clear cases of volume depletion. Finally, renal transplantation appears to confer a survival advantage to dialysis in SCD patients and should be pursued when possible.

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“…14,15,18 In this study, 15 mg/kg dose of DFX was used, which was consistent with that used in other studies in patients with kidney disease. 28,29 DFX has been shown to be generally well tolerated in adults and children with different chronic anemias. 30 Common AEs reported in this study included gastrointestinal disturbances and rash, which are consistent with those observed in other studies with DFX.…”

Section: Discussionmentioning

confidence: 98%

Long-term effects of an oral iron chelator, deferasirox, in hemodialysis patients with iron overload

2014

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Background/Purpose Retention of excess iron from transfused blood in organs in patients with renal anemia may lead to various systemic complications. Iron chelating agents such as deferasirox (DFX) decrease such iron overload. This study assessed the efficacy, safety, and tolerability of DFX in hemodialysis (HD) patients with iron overload. Methods We retrospectively (February 2008 to June 2012) reviewed data for eight HD patients with end-stage renal disease who were prescribed DFX (15 mg/kg/day) for transfusion-induced iron overload. Baseline and post-treatment levels of hematocrit, ferritin, erythropoietin (EPO), transferrin saturation (TSAT), total and unsaturated iron-binding capacity (TIBC and UIBC, respectively), and blood transfusion volumes were measured. Treatment efficacy was evaluated by observing changes in ferritin and TSAT during the study period; monthly EPO doses and blood transfusions were also recorded. Safety was evaluated in the form of adverse events. Results DFX administration caused statistically significant reductions in TSAT (68.2-49.2%; P = 0.036) and ferritin (3133.1-1215.6 ng/ml; P = 0.017). Significant post-treatment increases in UIBC (63.3-196.6 µg/dl; P = 0.018) and TIBC (210.0-422.4 µg/dl; P = 0.012) were also observed. While there were no significant differences in hematocrit values or EPO requirements after treatment, significant reductions in average monthly transfusion volumes (P = 0.026) were recorded. DFX was generally well tolerated; common adverse effects included nausea, vomiting, diarrhea, and abdominal pain. Conclusion DFX significantly improved iron metabolism in HD patients with iron overload and had an acceptable frequency of adverse effects.

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Pharmacokinetics and safety of deferasirox in subjects with chronic kidney disease undergoing haemodialysis

Cited by 17 publications

References 28 publications

Association between renal iron accumulation and renal interstitial fibrosis in a rat model of chronic kidney disease

Association between renal iron accumulation and renal interstitial fibrosis in a rat model of chronic kidney disease

Management of the Dialysis Patient with Sickle Cell Disease

Long-term effects of an oral iron chelator, deferasirox, in hemodialysis patients with iron overload

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