Effective Phosphate Binder Research Articles

Development of potent non-acylhydrazone inhibitors of intestinal sodium-dependent phosphate transport protein 2b (NaPi2b)

Inhibition of intestinal sodium-dependent phosphate transport protein 2b (NaPi2b), responsible for intestinal phosphate absorption, is considered to reduce serum phosphate levels, making it a promising therapeutic approach for hyperphosphatemia. Previously, we aimed to identify new drugs for hyperphosphatemia treatment and obtained zwitterionic compound 3 (IC50 = 64 nM) as a potent selective inhibitor of intestinal NaPi2b. This small-molecule compound is gut-restricted owing to its almost membrane-impermeable property. However, when compound 3, containing an acylhydrazone structure, is exposed to plasma, it is easily metabolized and likely produces an acetylhydrazine compound. Clinical studies have shown that acetylhydrazine is a risk factor for hepatic toxicity owing to its microsomal metabolism, wherein toxic reactive intermediates are formed.Therefore, in this study, we aimed to obtain potent NaPi2b inhibitors without an acylhydrazone structure to reduce the risk of hepatic toxicity. We developed compound 18, an anilide compound with zwitterionic property having potent phosphate uptake inhibitory activity in vitro (IC50 = 14 nM) and low bioavailability (FaFg = 5.9%). Oral administration of compound 18 in rats showed a reduction in phosphate absorption comparable to that observed with lanthanum carbonate, a clinically effective phosphate binder used in hyperphosphatemia treatment. Moreover, combined administration of compound 18 and lanthanum carbonate resulted in an additive effect on phosphate absorption inhibition in rats. Our findings suggest that combination therapy with lanthanum carbonate and compound 18 will not only provide better treatment outcomes for hyperphosphatemia but also reduce gastrointestinal side effects in patients.

The influence of poly(allylamine hydrochloride) hydrogel crosslinking density on its thermal and phosphate binding properties

Sevelamer hydrochloride (SH) or Renagel® is an effective phosphate binder prescribed to prevent the absorption of phosphate in end stage renal disease (ESRD) patients. The relationship between SH structure and binding capacity and affinity is very important and can be used in characterising the sensitivity of the hydrogel to binding conditions. Thus, a series of hydrogels were prepared by varying the amount of crosslinker, whilst the other hydrogel components were kept constant. Variation of this parameter influenced the hydrogel structure as shown by swelling data, differential scanning calorimetry and solid state nuclear magnetic resonance spectroscopy. The hydrogels’ physical characteristics were found to correlate with the number of phosphate binding sites and affinity obtained from the Langmuir–Freundlich Isotherm (L–FI) and affinity distribution spectra (AD). The hydrogels formed using lower amounts of crosslinker showed a slight increase in binding capacity but with lower affinity. However, the influence of the pH of the binding media on the binding parameters of sevelamer hydrochloride was significant. This is the first report on the use of AD spectra generated from L-FI binding parameters in hydrogels, which demonstrates the sensitivity of the affinity and binding site numbers to changes in hydrogel physical properties and the pH of the binding media.

Renoprotective effects of ferric citrate in a mouse model of chronic kidney disease

In chronic kidney disease, ferric citrate has been shown to be an effective phosphate binder and source of enteral iron; however, the effects of ferric citrate on the kidney have been less well-studied. Here, in Col4α3 knockout mice—a murine model of progressive chronic kidney disease, we evaluated the effects of five weeks of 1% ferric citrate dietary supplementation. As expected, ferric citrate lowered serum phosphate concentrations and increased serum iron levels in the Col4α3 knockout mice. Consistent with decreased enteral phosphate absorption and possibly improved iron status, ferric citrate greatly reduced circulating fibroblast growth factor 23 levels. Interestingly, ferric citrate also lessened systemic inflammation, improved kidney function, reduced albuminuria, and decreased kidney inflammation and fibrosis, suggesting renoprotective effects of ferric citrate in the setting of chronic kidney disease. The factors mediating possible ferric citrate renoprotection, the mechanisms by which they may act, and whether ferric citrate affects chronic kidney disease progression in humans deserves further study.

Long-term safety and efficacy of ferric citrate in phosphate-lowering and iron-repletion effects among patients with on hemodialysis: A multicenter, open-label, Phase IV trial.

We explored the long-term safety and efficacy of ferric citrate in hemodialysis patients in Taiwan, and further evaluated the iron repletion effect and change of iron parameters by different baseline groups. This was a 12-month, Phase IV, multicenter, open-label study. The initial dose of ferric citrate was administered by patients' clinical condition and further adjusted to maintain serum phosphorus at 3.5-5.5 mg/dL. The primary endpoint was to assess the safety profiles of ferric citrate. The secondary endpoints were to evaluate the efficacy by the time-course changes and the number of subjects who achieved the target range of serum phosphorus. A total of 202 patients were enrolled. No apparent or unexpected safety concerns were observed. The most common treatment-emergent adverse events were gastrointestinal-related with discolored feces (41.6%). Serum phosphorus was well controlled, with a mean dose of 3.35±1.49 g/day, ranging from 1.5 to 6.0 g/day. Iron parameters were significantly improved. The change from baseline of ferritin and TSAT were 227.17 ng/mL and 7.53%, respectively (p-trend<0.001), and the increase started to slow down after 3-6 months of treatment. In addition, the increase trend was found only in patients with lower baseline level of ferritin (≤500 ng/mL) and TSAT (<30%). Ferric citrate is an effective phosphate binder with favorable safety profile in ESRD patients. The iron-repletion by ferric citrate is effective, and the increase is limited in patients with a higher baseline. In addition to controlling hyperphosphatemia, ferric citrate also shows additional benefits in the treatment of renal anemia. ClinicalTrials.gov ID: NCT03256838; 12/04/2017.

Effect of Phosphate Binders and a Dietary Iron Supplement on the Pharmacokinetics of a Single Dose of Vadadustat in Healthy Adults.

Vadadustat is a hypoxia‐inducible factor prolyl‐hydroxylase inhibitor being developed for the treatment of anemia in patients with chronic kidney disease. Sequelae of chronic kidney disease include hyperphosphatemia and anemia, which are frequently treated with phosphate binders and iron supplements, respectively. Two studies evaluating the pharmacokinetics, safety, and tolerability of a single oral dose of vadadustat coadministered with a phosphate binder or iron supplement were conducted in healthy adult participants. In study 1, 54 healthy women and men were administered vadadustat (300 mg) alone and 1 hour before, concurrently with, or 2 hours after a phosphate binder (sevelamer carbonate 1600 mg, calcium acetate 1334 mg, or ferric citrate 2000 mg). In study 2, 10 healthy men were administered vadadustat (450 mg) alone and concomitantly with the oral iron supplement ferrous sulfate (325 mg [equivalent to 65 mg of elemental iron]). Vadadustat exposure was reduced by coadministration with sevelamer carbonate, calcium acetate, ferric citrate, or ferrous sulfate. Geometric least squares mean ratios for area under the concentration‐time curve from time 0 to infinity were reduced 37% to 55% by phosphate binders and 46% by ferrous sulfate. However, when vadadustat was administered 1 hour before phosphate binders, 90% confidence intervals for vadadustat exposure were within the no‐effect boundaries of +50% to –33%, indicating that drug‐drug interactions can be reduced by administering vadadustat 1 hour before phosphate binders. Vadadustat was well tolerated when administered in conjunction with phosphate binders or an iron supplement.

Effects of phosphate binders on bone biomarkers and bone density in haemodialysis patients.

The incidences of osteoporosis, fracture and vascular calcification increase concordantly with the progression of chronic kidney disease (CKD). CKD-mineral bone disease (CKD-MBD) induced by hyperphosphatemia is a major pathophysiologic mechanism. The effects of phosphate binders on bone turnover biomarkers and bone mineral density (BMD) in haemodialysis patients are still inconclusive. Our aim is to demonstrate the effects of these phosphate binders on different aspects of CKD-MBD. We conducted a prospective cohort of 65 haemodialysis patients to investigate the effect of 12-month monotherapy of phosphate binders composing calcium-based phosphate binders (CPB) or non-calcium-based phosphate binders (NCPB), including sevelamer and lanthanum, on bone turnover biomarkers and BMD changes. The performance of bone turnover biomarkers to predict low BMD was attentively determined. When compared with CPB, NCPB use was associated with higher levels of bone turnover biomarkers. NCPB was also associated with lower BMD at lumbar and distal radius. Total procollagen type 1N-terminal propeptide (P1NP), bone-specific alkaline phosphatase (BALP), and tartrate-resistant acid phosphatase 5b (TRAP5b) provided the best performance for diagnosing low BMD in haemodialysis patients. Switching from CPB to NCPB might increase bone biomarkers and prevent the development of adynamic bone disease. On the contrary, NCPB should be cautiously used in haemodialysis patients who already had low BMD. P1NP, BALP and TRAP5b could be used to guide the appropriate management, including anti-resorptive and anabolic medications, and predict low BMD in haemodialysis patients treated with phosphate binders.

Discovery of Gut-Restricted Small-Molecule Inhibitors of Intestinal Sodium-Dependent Phosphate Transport Protein 2b (NaPi2b) for the Treatment of Hyperphosphatemia.

NaPi2b is primarily expressed in the small intestine, lungs, and testes and plays an important role in phosphate homeostasis. The inhibition of NaPi2b, responsible for intestinal phosphate absorption, is considered to reduce serum phosphate levels, making it a promising therapeutic approach for hyperphosphatemia. Using a novel phosphate uptake inhibitor 3 (IC50 = 87 nM), identified from an in-house compound collection in human NaPi2b-transfected cells as a prototype compound, we conducted its derivatization based on a Ro5-deviated strategy to develop orally administrable small-molecule NaPi2b inhibitors with nonsystemic exposure. Consequently, compound 15, a zwitterionic compound with a potent in vitro phosphate uptake inhibitory activity (IC50 = 64 nM) and a low membrane permeability (Pe < 0.025 × 10-6 cm/s), was developed. Compound 15 showed a low bioavailability (F = 0.1%) in rats and a reduction in phosphate absorption in the rat intestinal loop assay comparable to sevelamer hydrochloride, a clinically effective phosphate binder for treating hyperphosphatemia.

P1411THE EFFICACY AND SAFETY OF THE SUCROFFERRIC OXYHYDXIDE IN HEMODIALYSIS PATIENTS : RESULTS OF A PROSPECTIVE RANDOMIZED CONTROLLED TRIAL

Abstract Background and Aims The treatment of hyperphosphatemia is the main goal in the treatment of mineral and bone disorders in patients with CKD. However, the results of the correction of hyperphosphatemia remain unsatisfactory. This is due to the absence of effective and safe medicines. In our prospective randomized controlled trial were evaluated the effects of a 16-week treatment with new phosphate binder - sucroferric oxyhydroxide and a sevelamer carbonate (“sevelamer”) on CKD-MBD parameters in patients on hemodialysis with hyperphosphatemia. Method After a 2-4-week washout period from previous phosphate binders, 50 stable patients with hyperphosphatemia (P &amp;gt; 5.5 mg / dl) were randomized at a 1: 1 ratio to receive sucroferric oxyhydroxide (n = 25) or sevelamer (n = 25) for treatment up to 16 weeks. In all patients were evaluated levels of P, Ca, PTH, ferritin, transferrin saturation, Hb, FGF-23, soluble Klotho, CRP - monthly. The dose of both medications was adjusted according to serum phosphate. Results Phosphate binder therapy of sucroferric oxyhydroxide was associated with a significant decrease in serum phosphate from 6.8 ± 1.5 to 5.27 ± 0.99 mg/dl (p &amp;lt;0.01); however, treatment with sevelamer did not decrease in the level of P: 6.32 ± 1.5 vs 6.35 ± 1.9 mgl/dl. The number of tablets was lower in the sucroferric oxyhydroxide group (mean ± SD 2.0 ± 1.5 tablets / day) compared with sevelamer (mean ± SD 6.1 ± 3.2 tablets / day). The average intact fibroblast growth factor-23 (FGF-23), PTH, transferrin saturation and ferritin did not significantly change in both groups. Klotho changed only in patients received sucroferric oxyhydroxide, an increase of 25% (р &amp;lt; 0.05) and we also noted in this group an increase in Hb level from 105.6 ± 15.7 to 111.9 ± 22.3 g/l (p &amp;lt;0.05) by the end of the study, simultaneously level of CRP significantly decreased (P &amp;lt; 0.01) by 50% . During the study, 6 patients in the group with sucroferric oxyhydroxide and 5 in the sevelamer group dropped out due to dyspeptic symptoms. Conclusion Sucroferric oxyhydroxide is a new effective phosphate binder with a comparable safety profile to a sevelamer. Treatment with this drug can significantly increase the level of Hb, and Klotho and reduce level of inflammation.

What is the most effective phosphate binder to treat hyperphosphatemia in patients with CKD who are not on dialysis?

What is the most effective phosphate binder to treat hyperphosphatemia in patients with CKD who are not on dialysis?

Study in Healthy Adult Subjects to Assess the Effect of Phosphate Binders on the Pharmacokinetics of a Single Dose of Vadadustat

Study in Healthy Adult Subjects to Assess the Effect of Phosphate Binders on the Pharmacokinetics of a Single Dose of Vadadustat

Phosphate binders in chronic kidney disease: an updated narrative review of recent data.

Chronic kidney disease (CKD) is frequently accompanied by hyperphosphatemia. High serum phosphate usually requires dietary measures, adequate dialysis prescription and/or phosphate binders. For this narrative review a PubMed searched was undertaken to identify new publications on phosphate binders that had been published between January 2015 and July 2019. The present review summarizes this most recent information on dietary measures and their problems in treating hyperphosphatemia in CKD patients, overall effects of phosphate binders on cardiovascular mortality and morbidity, adherence to phosphate binder therapy as well as new data on specific aspects of the various phosphate binders on the market: calcium-containing phosphate binders, polymeric phosphate binders (sevelamer, bixalomer, colestilan), magnesium-containing phosphate binders, lanthanum carbonate, ferric citrate, sucroferric oxyhydroxide, and new compounds in development, in particular drugs targeting intestinal phosphate transporters.

A comparison between the combined effect of calcium carbonate with sucroferric oxyhydroxide and other phosphate binders: an in vitro and in vivo experimental study

BackgroundApproximately 30% of patients on dialysis received combination therapy for their phosphate binder prescription; however, few studies for combined effects of phosphate binders are reported. For the purpose of evaluating the efficacy of combination therapy, we compared the efficacy of sucroferric oxyhydroxide (PA21) combined with calcium carbonate with that of lanthanum carbonate hydrate, sevelamer hydrochloride, and ferric citrate hydrate combined with calcium carbonate.MethodsFor in vitro studies, calcium carbonate and the other phosphate binders alone or in combination were stirred in phosphate solution at pH 2–8 for 2 h. After centrifuging the suspension, the phosphorus level in the supernatant was determined. For in vivo studies, rats were orally administered calcium carbonate and the other phosphate binders (except for sevelamer hydrochloride) alone or in combination, followed by oral administration of phosphate solution adjusted to pH 2 or 7. Serum samples were collected from the rats at predetermined timepoints and the serum phosphorus levels were determined and analyzed using a two-way analysis of variance.ResultsIn the in vitro study, the measured phosphate-binding capacity of combining sevelamer hydrochloride, PA21, and lanthanum carbonate hydrate with calcium carbonate was approximately equal to or greater than the theoretical values under most conditions. Furthermore, these combined effects were insensitive to pH in that order. The measured phosphate-binding capacity of ferric citrate hydrate combined with calcium carbonate was smaller than the theoretical values, and the combination did not exhibit efficacy under any of the tested conditions. In the in vivo study, the combined effect of PA21 and calcium carbonate at both pH values and that of lanthanum carbonate hydrate and calcium carbonate at pH 2 were additive. In contrast, the combined effect of lanthanum carbonate hydrate and calcium carbonate at pH 7 and that of ferric citrate hydrate and calcium carbonate at pH 2 were antagonistic.ConclusionsThese results suggest that coadministration of PA21 and calcium carbonate showed good and relatively stable efficacy throughout the range of the gastrointestinal pH and that combining lanthanum carbonate hydrate and ferric citrate hydrate with calcium carbonate may not produce the expected efficacy under certain conditions.

Effectiveness of phosphate binders in adult patients with end stage renal disease receiving hemodialysis: a systematic review.

The objective of the review was to evaluate the effectiveness of the use of phosphate binders on mortality and serum levels of phosphorus, calcium and parathyroid hormone in adult patients with end stage renal disease receiving hemodialysis compared to hemodialysis with no phosphate binder use. End stage renal disease leading to hemodialysis is a common global health issue. Effective management of this population is focused on balancing alterations in bone mineral markers such as phosphorus, calcium and parathyroid hormone. Chronic imbalances are associated with all-cause mortality. Phosphate binders are a crucial element to regulating these levels. The review considered studies including adult patients, age 18 and over, receiving hemodialysis. The intervention of interest was the use of any drug within the class of phosphate binders. Outcomes of interest were all-cause mortality and serum levels of phosphorus, calcium and parathyroid hormone. Experimental and quasi-experimental study designs were considered. A search for relevant published and unpublished literature was conducted through November 5, 2017. Databases searched included PubMed, CINAHL, Embase and Cochrane Central Register of Controlled Trials (CENTRAL), in addition to gray literature sources. Articles that met the inclusion criteria were further assessed for methodological validity by two independent reviewers using the standard critical appraisal instruments from Joanna Briggs Institute. Data were extracted from papers included in the review using the standardized data extraction tool from the Joanna Briggs Institute. Quantitative data were pooled for statistical meta-analysis to evaluate the impact of phosphate binders on phosphorus and calcium. Seven studies were included in this review. A meta-analysis of four studies showed that the use of phosphate binders resulted in a statistically significant decrease in phosphorus levels compared to placebo (mean difference -1.89 mg/dL, 95% confidence interval -2.03 mg/dL, -1.75 mg/dL); three additional studies described narratively also showed a statistically significant decrease in phosphorus. A meta-analysis of three studies showed a statistically significant increase in calcium compared to placebo (mean difference 0.57 mg/dL, 95% confidence interval 0.50 mg/dL, 0.64 mg/dL); two additional studies described narratively showed no difference in effect on calcium. Of the three studies that measured parathyroid hormone, one showed a statistically significant improvement with the use of phosphate binders (mean difference -83.0 pg/mL, 95% confidence interval -154.63 pg/mL, -11.37 pg/mL) and two showed no difference in effect. No studies measured mortality. Phosphate binders are effective in reducing serum phosphorus. The findings on parathyroid hormone and calcium did not provide adequate support for phosphate binder use. The impact on mortality was not directly measured in any of the included studies.

Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD).

Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD).

Effectiveness of phosphate binders in adult patients with end stage renal disease receiving hemodialysis: a systematic review protocol.

The question of this review is what is the effectiveness of the use of phosphate binders on mortality and serum levels of phosphorus, calcium and intact parathyroid hormone in adult patients with end stage renal disease receiving hemodialysis?

Comparative analysis of the phosphate-binding effects of sucroferric oxyhydroxide, ferric citrate, and lanthanum carbonate

BackgroundIron-based phosphate binders are widely used in hemodialysis, to avoid the increased mortality associated with high serum phosphate in dialysis patients. However, comparative studies on the effects of phosphate binders are currently limited. In the present study, a comparative analysis of ferric citrate (FC), sucroferric oxyhydroxide (SF), and lanthanum carbonate (LC) was performed to assess their primary phosphate-binding and secondary iron uptake capacities.MethodsPatients on maintenance hemodialysis visit our group clinics regularly. The FC, SF, and LC groups comprised 101, 82, and 126 patients, respectively. Subjects were observed from December 2015 to April 2016 (5 months).Serum phosphate levels and other markers were measured in the three medication groups, and changes in phosphate levels and other clinical markers were compared. A drug treatment was considered to be effective if the serum phosphate levels of the patient decreased from baseline in each of the drugs. We evaluated the phosphate-binding capacity compared with each drug using a mixed effect model, for adjusted repeated measured analysis.ResultsSF showed higher phosphate-binding capacity than FC and LC. FC, SF, and LC showed no significant difference in phosphate-binding capacity in the adjusted mixed effect model. However, patients in the FC group exhibited iron accumulation.ConclusionSucroferric oxyhydroxide possesses better phosphate-binding efficacies than ferric citrate and lanthanum carbonate. In addition, ferric citrate showed a strong iron-cumulative effect.

Erratum to: Effects of lanthanum carbonate and calcium carbonate on fibroblast growth factor 23 and hepcidin levels in chronic hemodialysis patients.

Phosphate binders have an impact on fibroblast growth factor 23 (FGF23); however, the effect of phosphate binders on serum hepcidin has not been explored. We conducted a 24-week multicenter randomized controlled trial to investigate the effects of lanthanum carbonate or calcium carbonate monotherapy on serum phosphate, FGF23, and hepcidin levels in chronic hemodialysis patients. Forty-six patients were recruited, and daily dietary phosphorus was controlled between 600–800 mg. Serum calcium, phosphate, albumin, alkaline phosphatase (ALP), FGF23, intact parathyroid hormone (iPTH), hepcidin, high-sensitivity CRP (hsCRP), 25(OH)D, 1,25(OH)2D, fetuin-A, and osteopontin were checked as scheduled. Twenty-five patients completed the study. Mean serum FGF23 level was significantly decreased after a 24-week treatment with lanthanum (8677.5 ± 7490.0 vs. 4692.8 ± 5348.3 pg/mL, p = 0.013, n = 13), but not with calcium (n = 12). The reduction of serum hepcidin in lanthanum group was positively correlated with the decrement of serum phosphate (r = 0.631, p = 0.021) and serum hsCRP (r = 0.670, p = 0.012) levels, respectively. Serum ALP, iPTH, vitamin D, fetuin-A, and osteopontin revealed no significant inter- or intragroup differences. In summary, a decrease in serum FGF23 levels and a trend of decline in hepcidin levels were observed only in lanthanum group.

Effects of phosphate binders on the gastrointestinal absorption of arsenate and of an SGLT2 inhibitor drug on the urinary excretion of arsenite in mice

Arsenate (AsV) and arsenite (AsIII) are typical sources of acute and chronic arsenic poisoning. Therefore, reducing inner exposure to these arsenicals is a rational objective. Because AsV mimics phosphate, phosphate binder drugs may decrease the intestinal AsV absorption. Indeed, lanthanum and aluminium salts and sevelamer removed AsV from solution in vitro, especially at acidic pH. In mice gavaged with AsV, lanthanum chloride, lanthanum carbonate and aluminium hydroxide given orally also lowered the urinary excretion and tissue levels of AsV and its metabolites, indicating that they decreased the gastrointestinal AsV absorption. As some glucose transporters may carry AsIII, the effect of the SGLT2 inhibitor dapagliflozin was investigated in AsIII-injected mice. While producing extreme glucosuria, dapagliflozin barely affected the urinary excretion and tissue concentrations of AsIII and its metabolites. Thus, phosphate binders (especially lanthanum compounds) can reduce the gastrointestinal absorption of AsV; however, SGLT2 inhibition cannot diminish the renal reabsorption of AsIII.

Preclinical studies of VS-505: a non-absorbable highly effective phosphate binder.

Phosphate imbalance is often present in chronic kidney disease (CKD), and it contributes to a higher cardiovascular mortality rate. A phosphate binder is typically part of a treatment strategy for controlling phosphate imbalance. However, safety concerns and low compliance are two well-recognized disadvantages of on-market phosphate binders. This report describes the preclinical studies of VS-505, a non-absorbable, calcium- and aluminum-free, plant-derived polymer currently being evaluated in haemodialysis patients in Australia. Normal Sprague Dawley (SD) rats or uraemic SD rats induced by 5/6 nephrectomy fed a high-phosphate diet were treated with VS-505 or sevelamer (0.05-10% in food) for 5 and 28days respectively. Urinary and serum phosphate levels were significantly elevated in untreated rats, and were decreased by VS-505 and sevelamer. VS-505 increased faecal phosphate levels in a dose-dependent manner. High-phosphate diet also caused an increase in serum FGF-23 and parathyroid hormone in nephrectomized (NX) rats, effects prevented by VS-505 or sevelamer. Significant aortic calcification was observed in NX rats treated with 5% sevelamer, whereas VS-505 at all doses tested did not show effects. VS-505 had no effects on small intestine histomorphology and intestinal sodium-dependent phosphate cotransporter gene expression. In vitro characterizations showed that VS-505 has a relatively high density and low expansion volume when exposed to simulated gastric fluid. VS-505 is a safe and effective phosphate binder and may offer the advantage of having a reduced pill burden and minimal GI side effects for CKD patients.

Long-term observational study in Japanese hemodialysis patients who completed a 3-year clinical study of lanthanum carbonate

Lanthanum carbonate (LC), an effective phosphate (P) binder, is widely used to manage hyperphosphatemia in hemodialysis patients. However, the long-term safety of LC treatment in clinical practice has not been completely established. In an observational multicenter study, we retrospectively investigated the long-term tolerability in Japanese hemodialysis patients who had completed a 3-year phase III extension study of LC. Among 39 patients who completed the phase III extension study, those who gave written informed consent to allow a retrospective examination of their medical records for up to 8 years were enrolled. During the period spanning 2009 to 2013, a tolerability assessment was performed by monitoring adverse events, laboratory parameters, and vital signs. Among the 34 enrolled patients, 30 were included for analysis. In this 5-year follow-up observational study, 18 of 30 patients (60.0 %) received LC with or without some other P binders (PBs), 10 patients (33.3 %) switched from LC to another PB, and 2 patients (6.7 %) did not use PB. During the phase III study, 16 patients (53.3 %) experienced a drug-related adverse event, with the most common being gastrointestinal disorder, already known to be a common adverse event of LC. No drug-related adverse events were reported during the follow-up observational study. Five of 18 patients (27.8 %) who continued LC and 3 of 12 patients (25.0 %) who did not continue LC experienced serious adverse events during the follow-up observational study. However, none of these events except for constipation were drug-related. Mean serum P concentrations was kept within the guideline-recommended management target range during the study period. No clinically significant changes in laboratory parameters and vital signs were observed except for pronounced decreases in intact parathyrois hormone (PTH) and blood pressure during the follow-up observational study period. In patients who completed a 3-year phase III extension study of LC, there was no evidence of delayed adverse events or any increase in the incidence of LC-related adverse events with increasing LC exposure for up to 8 years. UMIN-CTR UMI15227