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Kidney International. Supplement Dec 2009Hyperphosphatemia is a central characteristic feature of chronic kidney disease-mineral and bone disorder (CKD-MBD). Phosphorus excess is an independent cardiovascular... (Review)
Review
Hyperphosphatemia is a central characteristic feature of chronic kidney disease-mineral and bone disorder (CKD-MBD). Phosphorus excess is an independent cardiovascular risk factor for morbidity and mortality in patients with advanced CKD. Over the past 40 years, hyperphosphatemia has been a central therapeutic issue in advanced CKD. Mainstays of hyperphosphatemia treatment are reduction of dietary phosphorus, use of phosphate binders, and optimized phosphorus removal via dialysis. Currently, several phosphate binders are approved for use (aluminum, calcium, lanthanum, sevelamer); all share a common functionality in that they bind phosphorus and reduce the amount absorbed in the gastrointestinal lumen. Over the last decade, nephrologists have debated the relative tolerability and efficacy of these agents, especially the potential for vascular calcification and cardiovascular risk reduction. Recent research has focused on the question of whether a metal-free, calcium-free, and non-absorbed binder, such as sevelamer, offers advantages over other binder types. Most notable may be the potential benefit of reducing calcium load. In addition, sevelamer has several additional pleiotropic effects that may extend its basic indication, some of which may help attenuate vascular calcification. These include effects on bone turnover and the link between abnormal vascular processes and bone metabolism (the so-called 'bone-vascular axis'), as well as lipid metabolism, and systemic inflammatory mediators such as fetuin-A. We review the evidence for these pleiotropic effects, and suggest these may help in some way to improve the substantial disease burden in the CKD-MBD population.
Topics: Animals; Bone and Bones; C-Reactive Protein; Calcinosis; Calcium; Humans; Hyperphosphatemia; Inflammation; Kidney Failure, Chronic; Lipid Metabolism; Polyamines; Renal Dialysis; Renal Insufficiency, Chronic; Sevelamer; alpha-Fetoproteins
PubMed: 19946324
DOI: 10.1038/ki.2009.404 -
Journal of Renal Nutrition : the... Jan 2020Phosphate binders are commonly prescribed in patients with end-stage kidney disease to prevent and treat hyperphosphatemia. These binders are usually associated with... (Review)
Review
Phosphate binders are commonly prescribed in patients with end-stage kidney disease to prevent and treat hyperphosphatemia. These binders are usually associated with gastrointestinal distress, may bind molecules other than phosphate, and may alter the gut microbiota, altogether having systemic effects unrelated to phosphate control. Sevelamer is the most studied of the available binders for nonphosphate-related effects including binding to bile acids, endotoxins, gut microbiota-derived metabolites, and advanced glycation end products. Other binders (calcium- and noncalcium-based binders) may bind vitamins, such as vitamin K and folic acid. Moreover, the relatively new iron-based phosphate binders may alter the gut microbiota, as some of the iron or organic ligands may be used by the gastrointestinal bacteria. The objective of this narrative review is to provide the current evidence for the nonphosphate effects of phosphate binders on gastrointestinal function, nutrient and molecule binding, and the gut microbiome.
Topics: Calcium; Chelating Agents; Gastrointestinal Tract; Humans; Hyperphosphatemia; Kidney Failure, Chronic; Phosphates; Sevelamer
PubMed: 30846238
DOI: 10.1053/j.jrn.2019.01.004 -
Journal of Food and Drug Analysis Mar 2023The Non-Biological Complex Drug (NBCD) Working Group defines an NBCD as "a medicinal product, not being a biological medicine, where the active substance is not a... (Review)
Review
The Non-Biological Complex Drug (NBCD) Working Group defines an NBCD as "a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by physicochemical analytical means". There are concerns about the potential clinical differences between the follow-on versions and the originator products and within the individual follow-on versions. In the present study, we compare the regulatory requirements for developing generic products of NBCDs in the European Union (EU) and the United States (US). The NBCDs investigated included nanoparticle albumin-bound paclitaxel (nab-paclitaxel) injections, liposomal injections, glatiramer acetate injections, iron carbohydrate complexes, and sevelamer oral dosage forms. The demonstration of pharmaceutical comparability between the generic products and the reference products through comprehensive characterization is emphasized for all product categories investigated. However, the approval pathways and detailed requirements in terms of non-clinical and clinical aspects may differ. The general guidelines in combination with product-specific guidelines are considered effective in conveying regulatory considerations. While regulatory uncertainties still prevail, it is anticipated that through the pilot program established by the European Medicines Agency (EMA) and the FDA, harmonization of the regulatory requirements will be achieved, thereby facilitating the development of follow-on versions of NBCDs.
Topics: Biological Products; Sevelamer
PubMed: 37224550
DOI: 10.38212/2224-6614.3441 -
Journal of Nephrology Apr 2022Hyperphosphatemia is a common complication in dialysis-dependent patients with chronic kidney disease. Most dialysis-dependent patients need oral phosphate binder... (Review)
Review
Hyperphosphatemia is a common complication in dialysis-dependent patients with chronic kidney disease. Most dialysis-dependent patients need oral phosphate binder therapy to control serum phosphorus concentrations. Most phosphate binders have a high daily pill burden, which may reduce treatment adherence and impair phosphorus control. Sucroferric oxyhydroxide is a potent iron-based phosphate binder approved for use in dialysis-dependent patients in 2013. A randomized controlled trial of sucroferric oxyhydroxide demonstrated its efficacy for reduction of serum phosphorus with a lower pill burden than sevelamer carbonate. Clinical trials carefully select patients, monitor adherence, and routinely titrate medications to a protocol-defined goal. Consequently, trials may not reflect real-world use of medications. Since its approval, we and others have performed retrospective and prospective analyses of sucroferric oxyhydroxide in real-world clinical practice in > 6400 hemodialysis and approximately 500 peritoneal dialysis patients in the USA and Europe. Consistent with the clinical trial data, real-world observational studies have demonstrated that sucroferric oxyhydroxide can effectively reduce serum phosphorus with a lower daily pill burden than most other phosphate binders. These studies have also shown sucroferric oxyhydroxide provides effective serum phosphorus control in different treatment settings, including as monotherapy in phosphate binder-naïve patients, in patients switching from other phosphate binders, or when used in combination with other phosphate binders. These observational studies indicate a favorable safety and tolerability profile, and minimal, if any, systemic iron absorption. This article reviews the key results from these observational studies of sucroferric oxyhydroxide and evaluates its role in the management of hyperphosphatemia in clinical practice.
Topics: Drug Combinations; Ferric Compounds; Humans; Hyperphosphatemia; Iron; Phosphates; Phosphorus; Prospective Studies; Randomized Controlled Trials as Topic; Renal Dialysis; Retrospective Studies; Sucrose
PubMed: 35138627
DOI: 10.1007/s40620-021-01241-5 -
Therapeutic Advances in Cardiovascular... Dec 2013Endothelial dysfunction underlies multiple cardiovascular consequences of chronic kidney disease (CKD) and antecedent diabetes or hypertension. Endothelial insults in... (Review)
Review
Endothelial dysfunction underlies multiple cardiovascular consequences of chronic kidney disease (CKD) and antecedent diabetes or hypertension. Endothelial insults in CKD or end-stage renal disease (ESRD) patients include uremic toxins, serum uric acid, hyperphosphatemia, reactive oxygen species, and advanced glycation endproducts (AGEs). Sevelamer carbonate, a calcium-free intestinally nonabsorbed polymer, is approved for hyperphosphatemic dialysis patients in the US and hyperphosphatemic stage 3-5 CKD patients in many other countries. Sevelamer has been observed investigationally to reduce absorption of AGEs, bacterial toxins, and bile acids, suggesting that it may reduce inflammatory, oxidative, and atherogenic stimuli in addition to its on-label action of lowering serum phosphate. Some studies also suggest that noncalcium binders may contribute less to vascular calcification than calcium-based binders. Exploratory sevelamer carbonate use in patients with stages 2-4 diabetic CKD significantly reduced HbA1c, AGEs, fibroblast growth factor (FGF)-23, and total and low-density lipoprotein (LDL) cholesterol versus calcium carbonate; inflammatory markers decreased and defenses against AGEs increased. Sevelamer has also been observed to reduce circulating FGF-23, potentially reducing risk of left ventricular hypertrophy. Sevelamer but not calcium-based binders in exploratory studies increases flow-mediated vasodilation, a marker of improved endothelial function, in patients with CKD. In contrast, lanthanum carbonate and calcium carbonate effects on FMV did not differ in hemodialysis recipients. The recent independent-CKD randomized trial compared sevelamer versus calcium carbonate in predialysis CKD patients (investigational in the US, on-label in European participants); sevelamer reduced 36-month mortality and the composite endpoint of mortality or dialysis inception. Similarly, independent-HD in incident dialysis patients showed improved survival with 24 months of sevelamer versus calcium-based binders. This review discusses recent exploratory evidence for pleiotropic effects of sevelamer on endothelial function in CKD or ESRD. Endothelial effects of sevelamer may contribute mechanistically to the improved survival observed in some studies of CKD and ESRD patients.
Topics: Animals; Cardiovascular Diseases; Chelating Agents; Endothelium, Vascular; Fibroblast Growth Factor-23; Humans; Kidney Failure, Chronic; Phosphates; Polyamines; Renal Insufficiency, Chronic; Risk Factors; Sevelamer; Treatment Outcome
PubMed: 24327730
DOI: 10.1177/1753944713513061 -
Hospital Pharmacy Apr 2016Hyperphosphatemia is a common problem in patients with chronic kidney disease (CKD). Calcium-containing phosphate binders are typically used as first-line therapy,...
BACKGROUND
Hyperphosphatemia is a common problem in patients with chronic kidney disease (CKD). Calcium-containing phosphate binders are typically used as first-line therapy, primarily due to cost considerations. Non-calcium phosphate binders such as sevelamer and lanthanum may be considered in the appropriate setting. It is hypothesized that lanthanum is less costly and has a lower pill burden compared to sevelamer carbonate.
OBJECTIVE
Determine the difference in cost (outcome 1) and tablet burden (outcome 2) between sevelamer carbonate and lanthanum within the Veteran population.
METHODS
Patients with an active prescription for lanthanum or sevelamer carbonate on October 22, 2014 were evaluated. Chi-square analysis was used to analyze categorical data, and 2-sided t test was used for continuous data. An α of 0.05 determined significance.
RESULTS
One hundred fifty patients were included in the evaluation. Patients were predominately male (96%) and had a diagnosis of end stage renal disease (ESRD; 78%). The combined rate of non-dialysis CKD (ND-CKD) stage 5 and ESRD was similar between lanthanum and sevelamer carbonate groups. Both groups achieved similar phosphorus control (56% vs 65%, with phosphorus level less than or equal to 5.5 mg/dL, respectively; P = .23). Lanthanum prescriptions required significantly fewer tablets per day (4 lanthanum tablets daily vs 7 sevelamer carbonate tablets daily; P < .001). A potential prescription cost savings of approximately $4,500 monthly or $54,000 annually was seen when considering conversion of patients in this study population from sevelamer carbonate to lanthanum therapy, with appreciable savings beginning at sevelamer daily doses of at least 4,800 mg.
CONCLUSIONS
Compared to sevelamer carbonate, lanthanum use was associated with reduced pill burden and lower absolute drug cost while maintaining similar phosphorus control.
PubMed: 27303079
DOI: 10.1310/hpj5104-312 -
International Journal of Nephrology and... 2014Phosphate control is still a great challenge in chronic kidney disease (CKD), and in spite of the great improvements in dialysis techniques, achievement of the goals for... (Review)
Review
Phosphate control is still a great challenge in chronic kidney disease (CKD), and in spite of the great improvements in dialysis techniques, achievement of the goals for mineral metabolism control is still far from ideal. Aluminum hydroxide has been largely abandoned due to the high risk of aluminum toxicity, while the use of calcium-based phosphate binders may cause hypercalcemia, overzealous parathyroid suppression, and extraskeletal calcification. Sevelamer hydrochloride has been introduced as an efficient medication for phosphate control, with a lower risk of hypercalcemia and parathyroid suppression. Various clinical trials have compared the risk of vascular calcification between sevelamer and calcium salts with inconsistent results. In spite of these inconsistencies, the Kidney Disease Outcomes Quality Initiative (KDOQI) suggests non-calcium phosphate binders as the preferred phosphate binder in dialysis patients with severe vascular and/or other soft-tissue calcifications and in those with hypercalcemia or parathyroid hormone (PTH) <150 mg/dL. The Kidney Disease Improving Global Outcome (KDIGO) limits the use of non-calcium phosphate binders to patients with hypercalcemia. Regarding the effect on mortality, the results of clinical trials are again inconsistent. The other important aspect of using sevelamer is the issue of price, which is substantially higher than calcium-based phosphate binders. Reviewing the studies on economic aspects shows that sevelamer increases quality-adjusted life-years (QALY) and possibly life years, with a higher cost compared to calcium-based phosphate binders. In conclusion, sevelamer is a very useful drug for phosphate control, reduction of hypercalcemia, and lessening the risk of adynamic bone disease, with probable reduction in vascular calcification and possible reduction in mortality rate. It has a higher economic burden on health care systems compared to calcium-based phosphate binders. This may affect its extensive use according to guideline recommendations, and will be influenced by local health care budgets and the decision of health care strategists.
PubMed: 24855385
DOI: 10.2147/IJNRD.S41626 -
Nephron 2024This study aimed to investigate the efficacy and safety of sucroferric oxyhydroxide (SFOH) versus sevelamer carbonate in controlling serum phosphorus (sP) in adult... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and Safety of Sucroferric Oxyhydroxide Compared with Sevelamer Carbonate in Chinese Dialysis Patients with Hyperphosphataemia: A Randomised, Open-Label, Multicentre, 12-Week Phase III Study.
INTRODUCTION
This study aimed to investigate the efficacy and safety of sucroferric oxyhydroxide (SFOH) versus sevelamer carbonate in controlling serum phosphorus (sP) in adult Chinese dialysis patients with hyperphosphataemia (sP >1.78 mmol/L).
METHODS
Open-label, randomised (1:1), active-controlled, parallel group, multicentre, phase III study of SFOH and sevelamer at starting doses corresponding to 1,500 mg iron/day and 2.4 g/day, respectively, with 8-week dose titration and 4-week maintenance (NCT03644264). Primary endpoint was non-inferiority analysis of change in sP from baseline to week 12. Secondary endpoints included sP over time and safety.
RESULTS
415 patients were screened; 286 were enrolled and randomised (142 and 144 to SFOH and sevelamer, respectively). Mean (SD) baseline sP: 2.38 (0.57) and 2.38 (0.52) mmol/L, respectively. Mean (SD) change in sP from baseline to week 12: - 0.71 (0.60) versus -0.63 (0.52) mmol/L, respectively; difference (sevelamer minus SFOH) in least squares means (95% CI): 0.08 mmol/L (-0.02, 0.18) with the lower limit of 95% CI above the non-inferiority margin of -0.34 mmol/L. The SFOH group achieved target sP (1.13-1.78 mmol/L) earlier than the sevelamer group (56.5% vs. 32.8% at week 4) and with a lower pill burden (mean 3.7 vs. 9.1 tablets/day over 4 weeks of maintenance, respectively). Safety and tolerability of SFOH was consistent with previous studies, and no new safety signals were observed.
CONCLUSION
SFOH effectively reduced sP from baseline and was non-inferior to sevelamer after 12 weeks of treatment but had a lower pill burden in Chinese dialysis patients with hyperphosphataemia; SFOH benefit-risk profile is favourable in Chinese patients.
Topics: Adult; Humans; Sevelamer; Hyperphosphatemia; Renal Dialysis; Ferric Compounds; Phosphorus; China; Chelating Agents; Drug Combinations; Sucrose
PubMed: 37473746
DOI: 10.1159/000531869 -
Frontiers in Bioengineering and... 2022As the most efficient method to treat hepatocellular carcinoma in the immediate or advanced stage, transarterial chemoembolization (TACE) is coming into the era of...
As the most efficient method to treat hepatocellular carcinoma in the immediate or advanced stage, transarterial chemoembolization (TACE) is coming into the era of microsphere (MP). Drug-eluting beads have shown their huge potential as an embolic agent and drug carrier for chemoembolization, but their sizes are strictly limited to be above 40 μm, which was considered to occlude vessels in a safe mode. microsphere smaller than 40 µm is easy to be washed out and transported to the normal liver lobe or other organs, causing severe adverse events and failed embolization. To determine whether sevelamer ultrafine particle (0.2-0.5 µm) is qualified as a safe and efficient embolic agent, we investigated the safety and therapeutic efficiency of transarterial sevelamer embolization (TASE) in the VX2 rabbit liver cancer model, aiming to challenge the "40 µm" rule on the selection criteria of the MP. In a four-arm study, blank bead (Callisphere, 100-300 µm), luminescent polystyrene microsphere (10, 100 µm), and sevelamer particle were transarterially administered to evaluate the threshold size of the MP size for intrahepatic or extrahepatic permeability. Another four-arm study was designed to clarify the safety and efficiency of preclinical transarterial sevelamer embolizationTASE tests over other techniques. Sham (saline), TASE, C-TACE, and D-TACE ( = 6) were compared in terms of serum chemistry, histopathology, and tumor necrosis ratio. In the first trials, the "40 µm" rule was detectable on the VX2 cancer model, but the regulation has no application to the new embolic agent as sevelamer ultrafine particles have not been found to leak out from the VX2 lesions, only found in the embolized vessels. Pathology proves that less viable tumor residue was found 2 weeks after the procedure, evidencing a better therapeutic outcome. No adverse events were found except for a short stress response. These results indicate that sevelamer is a safe and efficient embolic as an alternative to the current MP-based embolization therapy techniques.
PubMed: 36578505
DOI: 10.3389/fbioe.2022.1058042 -
Journal of the American Society of... Jan 2022Benefits of phosphate-lowering interventions on clinical outcomes in patients with CKD are unclear; systematic reviews have predominantly involved patients on dialysis.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Benefits of phosphate-lowering interventions on clinical outcomes in patients with CKD are unclear; systematic reviews have predominantly involved patients on dialysis. This study aimed to summarize evidence from randomized controlled trials (RCTs) concerning benefits and risks of noncalcium-based phosphate-lowering treatment in nondialysis CKD.
METHODS
We conducted a systematic review and meta-analyses of RCTs involving noncalcium-based phosphate-lowering therapy compared with placebo, calcium-based binders, or no study medication, in adults with CKD not on dialysis or post-transplant. RCTs had ≥3 months follow-up and outcomes included biomarkers of mineral metabolism, cardiovascular parameters, and adverse events. Outcomes were meta-analyzed using the Sidik-Jonkman method for random effects. Unstandardized mean differences were used as effect sizes for continuous outcomes with common measurement units and Hedge's g standardized mean differences (SMD) otherwise. Odds ratios were used for binary outcomes. Cochrane risk of bias and GRADE assessment determined the certainty of evidence.
RESULTS
In total, 20 trials involving 2498 participants (median sample size 120, median follow-up 9 months) were eligible for inclusion. Overall, risk of bias was low. Compared with placebo, noncalcium-based phosphate binders reduced serum phosphate (12 trials, weighted mean difference -0.37; 95% CI, -0.58 to -0.15 mg/dl, low certainty evidence) and urinary phosphate excretion (eight trials, SMD -0.61; 95% CI, -0.90 to -0.31, low certainty evidence), but resulted in increased constipation (nine trials, log odds ratio [OR] 0.93; 95% CI, 0.02 to 1.83, low certainty evidence) and greater vascular calcification score (three trials, SMD, 0.47; 95% CI, 0.17 to 0.77, very low certainty evidence). Data for effects of phosphate-lowering therapy on cardiovascular events (log OR, 0.51; 95% CI, -0.51 to 1.17) and death were scant.
CONCLUSIONS
Noncalcium-based phosphate-lowering therapy reduced serum phosphate and urinary phosphate excretion, but there was an unclear effect on clinical outcomes and intermediate cardiovascular end points. Adequately powered RCTs are required to evaluate benefits and risks of phosphate-lowering therapy on patient-centered outcomes.
Topics: Chelating Agents; Ferric Compounds; Humans; Hyperphosphatemia; Lanthanum; Phosphates; Renal Insufficiency, Chronic; Sevelamer
PubMed: 34645696
DOI: 10.1681/ASN.2021040554