bixalomer and Renal-Insufficiency--Chronic

Hyperphosphatemia is common in chronic kidney disease (CKD) and is treated by dietary measures, dialysis techniques and/or phosphate binders. For the present review PubMed was searched for new publications on phosphate binders appearing between January 2010 and October 2015. This review summarizes the latest information on non-pharmacological measures and their problems in lowering phosphate in CKD patients, effects of phosphate binders on morbidity and mortality, adherence to phosphate binder therapy as well as new information on specific aspects of the various phosphate binders on the market: calcium acetate, calcium carbonate, magnesium-containing phosphate binders, polymeric phosphate binders (sevelamer, bixalomer, colestilan), lanthanum carbonate, ferric citrate, sucroferric oxyhydroxide, aluminum-containing phosphate binders, and new compounds in development. The review also briefly covers the emerging field of drugs targeting intestinal phosphate transporters.

Topics: Drug Combinations; Ferric Compounds; Humans; Hyperphosphatemia; Lanthanum; Phosphates; Polyamines; Renal Insufficiency, Chronic; Sevelamer; Sucrose

Topics: Animals; Capsules; Chelating Agents; Clinical Trials, Phase III as Topic; Coronary Disease; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Phosphoric Acids; Polyamines; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Risk

Currently, calcium- or metal-containing phosphate binders are available to treat hyperphosphatemia in predialysis patients with chronic kidney disease. Bixalomer, a non-calcium, metal-free phosphate binder, has not been studied in these patients. We evaluated the efficacy and safety of bixalomer versus placebo for treatment of hyperphosphatemia in Japanese predialysis patients with chronic kidney disease. This multicenter, randomized, double-blind, phase 3 trial, randomized eligible patients 1:1 to receive bixalomer or placebo for 12 weeks. Bixalomer was started at 1500 mg/day and adjusted up to 7500 mg/day depending on serum phosphorus concentrations. The primary endpoint was change in serum phosphorus concentration from baseline to end of treatment. After a 4-week pre-investigational period, 163 patients (bixalomer: N = 81; placebo: N = 82) were randomized. The adjusted mean change (95% confidence interval) from baseline to end of treatment in serum phosphorus was significantly greater with bixalomer (-0.78 [-0.98, -0.57] mg/dL) versus placebo (0.20 [-0.00, 0.41] mg/dL); mean difference: -0.98 (-1.27, -0.69), P < 0.001. At end of treatment, 57.5% of bixalomer-treated patients achieved target serum phosphorus concentrations, mean serum intact parathyroid hormone and fibroblast growth factor-23 decreased, and there were no significant changes in corrected serum calcium. The safety and tolerability of bixalomer was similar to placebo. The most common drug-related adverse events were gastrointestinal (>24% patients per group). There was a significant increase in bicarbonate concentrations with bixalomer versus placebo (P = 0.003). Bixalomer was superior to placebo for hyperphosphatemia in Japanese predialysis patients with chronic kidney disease and may constitute a new treatment option.

Topics: Aged; Double-Blind Method; Female; Humans; Hyperphosphatemia; Male; Middle Aged; Polyamines; Renal Insufficiency, Chronic; Treatment Outcome

Hyperphosphatemia is a prognostic factor for morbidity and mortality in chronic kidney disease. Bixalomer (Kiklin® Capsules) is a non-absorbable polymer that decreases serum phosphate levels by binding phosphate in the gastrointestinal tract. This study was a multicenter, double-blind, randomized, placebo-controlled study to confirm the superiority of bixalomer to placebo for a 4-week treatment period in patients with chronic kidney disease on hemodialysis with hyperphosphatemia. Sevelamer hydrochloride (HCl), a similar non-absorbable polymer, was used as an active comparator for open-label as a reference without statistical comparison for efficacy and safety. The primary endpoint was the change in serum phosphorus level from baseline. The safety profile was also investigated. The number of subjects was 32 in the placebo group and 31 in each bixalomer group (1.5, 3.0 and 4.5 g/day), respectively. The baseline serum phosphorus level was 7.95 to 8.25 mg/dL. Bixalomer showed a significant decrease in serum phosphorus level at all doses compared with placebo, and the adjusted mean change in serum phosphorus level from the baseline to the end of treatment (at Week 4 or at the time of discontinuation) was +0.24 mg/dL in the placebo group, -0.75 mg/dL in the 1.5 g/day group, -1.32 mg/dL in the 3.0 g/day group, and -1.80 mg/dL in the 4.5 g/day group, showing a dose-dependent decrease in serum phosphorus level. The mean change in serum phosphorus level was -2.32 mg/dL in the sevelamer HCl group under the mean dose of 4.8 g/day. Major adverse events included constipation, hard feces, vomiting, etc.; however, none of the adverse events were serious or severe. Consequently, the superiority of bixalomer to placebo and its dose-dependency for treating hyperphosphatemia were confirmed (Clinical trial registration: NCT00505037).

Topics: Chelating Agents; Dose-Response Relationship, Drug; Double-Blind Method; Hyperphosphatemia; Japan; Phosphorus; Polyamines; Renal Dialysis; Renal Insufficiency, Chronic; Sevelamer; Treatment Outcome

Bixalomer, a metal-free, nonabsorbable phosphate binder, is approved in Japan to treat hyperphosphatemia in dialysis patients. Bixalomer is effective and has a favorable safety profile in predialysis patients with hyperphosphatemia. This study examined the long-term effectiveness and safety of bixalomer in predialysis patients with hyperphosphatemia. This was a 48-week, multicenter, open-label, phase 3 study in Japanese predialysis patients with hyperphosphatemia. Patients received bixalomer at an initial dose of 1500 mg/day, which was titrated to a maximum of 7500 mg/day depending on patients' serum phosphorus responses to bixalomer. A total of 105 patients received bixalomer treatment, and 39 completed the study. The most common reason for discontinuation was initiation of dialysis. Mean serum phosphorus concentrations decreased from 5.15 mg/dL at baseline to 4.67 mg/dL at Week 12 and then fluctuated slightly around this level until it reached 4.58 mg/dL at Week 48. The proportion of total patients achieving the target serum phosphorus concentration (≥2.5 to <4.6 mg/dL) increased after treatment to a maximum of 66.2% at Week 20 and subsequently decreased to 51.3% by Week 48. Most adverse events (AEs) occurred in the first 12 weeks of treatment. The incidence of AEs did not increase with long-term treatment. Common AEs reported included nasopharyngitis (29.5%), constipation (19%), and upper respiratory tract inflammation (12.4%). These findings suggest that long-term treatment with bixalomer is effective, well tolerated, and has no new safety concerns. Bixalomer may be an alternative treatment option for the long-term management of hyperphosphatemia in patients with chronic kidney diseases.

Topics: Female; Humans; Hyperphosphatemia; Male; Middle Aged; Polyamines; Renal Insufficiency, Chronic; Time; Treatment Outcome

In the present study, we evaluated the in vitro characteristics of bixalomer for phosphate binding and swelling and assessed the urinary phosphorus excretion and plasma phosphorus level-lowering effect of bixalomer. The maximum phosphate binding capacity was 6.49 mmol/g and was maximized at pH 6.09. In rats, consuming a high-phosphorus diet resulted in elevated urinary phosphorus excretion, while consuming a diet of bixalomer (0.3-9%) or sevelamer hydrochloride (sevelamer HCl; 3-9%) mixed with a high-phosphorus diet resulted in a dose-dependent reduction in urinary phosphorus excretion. Rats with adenine sulfate-induced chronic kidney disease (CKD) had plasma phosphorus levels of 14.9-18.8 mg/dl, while CKD rats administered a 3% bixalomer or 3% sevelamer HCl diet for 4 weeks had relatively decreased plasma phosphorus levels (6.86 ± 1.42 or 5.32 ± 0.27 mg/dl, respectively). Bixalomer elevated the lowered blood pH in acidemic CKD rats, while sevelamer HCl administration only exacerbated the acidemia. The swelling index, which represents water adsorption capacity, of bixalomer was measured by subtracting the dry weight from the hydrated wet weight of the polymer. The swelling index of bixalomer was four times lower than that of sevelamer HCl. Bixalomer was found to reduce the plasma phosphorus level in CKD rats by binding phosphate in the small intestine and reducing phosphate absorption. Bixalomer showed favorable characteristics of a smaller swelling index than sevelamer HCl and amelioration of metabolic acidosis. These findings suggest that bixalomer may be useful in treating hyperphosphatemia, with fewer gastrointestinal side effects and amelioration of metabolic acidosis than sevelamer HCl.

Topics: Adsorption; Animals; Hyperphosphatemia; Male; Phosphates; Phosphorus; Polyamines; Rats, Wistar; Renal Insufficiency, Chronic; Water

Topics: Humans; Hyperphosphatemia; Japan; Polyamines; Renal Dialysis; Renal Insufficiency, Chronic