Sevelamer Hydrochloride

Sevelamer (Renagel®), an orally administered metal-free cationic hydrogel polymer/resin that binds dietary phosphate in the gastrointestinal (GI) tract, is approved for use in the US, Europe and several other countries for the treatment of hyperphosphataemia in adult patients with end-stage renal disease (ESRD) on haemodialysis or peritoneal dialysis.

Clinical evidence shows that sevelamer was at least as effective as calcium acetate and calcium carbonate at controlling serum phosphorus, calcium-phosphorus product (Ca × P) and intact parathyroid hormone (iPTH) levels, but generally reduced serum calcium levels to a greater extent and was associated with a lower risk of hypercalcaemic episodes than calcium-based phosphate binders. Sevelamer appeared to slow the progression of cardiovascular calcification in patients with ESRD and also had a beneficial effect on serum low-density lipoprotein-cholesterol (LDL-C) levels. In patients receiving chronic haemodialysis, there was no between-group difference in all-cause mortality between sevelamer and calcium-based phosphate binder therapy in the primary efficacy analysis in the large (n >2100), 3-year DCOR trial; in the smaller (n = 109) nonblind RIND trial in patients new to dialysis, data suggest there is an overall survival benefit with sevelamer versus calcium-based phosphate binder treatment. The relative survival benefits and cost effectiveness of these phosphate binder therapies remains to be fully determined. Sevelamer treatment was generally as well tolerated as calcium acetate or calcium carbonate treatment. Overall, sevelamer is a valuable option for the management of hyperphosphataemia in patients with ESRD on haemodialysis.

Sevelamer particles increase in size in the GI tract and become too large to be absorbed systemically. After administration of a single oral dose to healthy volunteers, no drug is detected in the blood and only negligible amounts are detected in the urine. All of the sevelamer dose is excreted in the faeces over a 10-day period, with ≈90% excreted within the first 5 days.

Sevelamer may directly bind orally administered immunosuppressants and other lipophilic drugs and nutrients in the GI tract, and the drug has been shown to significantly reduce the absorption pharmacokinetics of mycophenolate mofetil (measured as mycophenolic acid) in renal transplant patients and those of ciprofloxacin in healthy volunteers. The drug did not appear to affect the single-dose pharmacokinetics of ciclosporin (cyclosporin) in renal transplant patients and those of enalapril, metoprolol, digoxin, warfarin or supplemental iron in healthy volunteers.

In fully published, randomized, controlled, multicentre trials (n ≥50 receiving sevelamer) of 8–104 weeks' duration in adult patients with ESRD and hyperphosphataemia receiving maintenance haemodialysis, therapy with sevelamer (4.9–6.9 g/day) was at least as effective as therapy with calcium acetate (4.6–7.1 g/day) or calcium carbonate (3.9–4.3 g/day) at controlling serum phosphorus, Ca × P and iPTH levels. However, compared with calcium-based phosphate binders, which caused calcium loading, sevelamer significantly reduced serum calcium levels and the incidence of hypercalcaemic episodes. Furthermore, therapy with sevelamer appeared to slow the progression of cardiovascular calcification and reduced serum LDL-C and total cholesterol levels in studies of up to 2 years' duration.

In the 3-year prospective, randomized, open-label DCOR trial in >2100 patients on haemodialysis, there was no between-group difference in the relative risk of all-cause mortality (primary endpoint), although sevelamer treatment significantly reduced this risk compared with calcium-based phosphate binder treatment in those aged ≥65 years and those treated for >2 years. There were no statistically significant between-group differences in cardiovascular disease morbidity rates. In the RIND study in patients new to haemodialysis (median 44-month follow-up), sevelamer therapy was associated with a significantly lower risk of all-cause mortality than treatment with calcium-based phosphate binders. A large (n ≈1370) retrospective study of a cohort of incidence dialysis patients also indicated that sevelamer treatment conferred a survival benefit compared with calcium carbonate treatment (mean follow-up 452 days).

The cost effectiveness of sevelamer relative to calcium-based phosphate binders remains to be fully determined.

Sevelamer was generally well tolerated in randomized controlled trials in patients with ESRD and hyperphosphataemia on haemodialysis, with a tolerability profile and compliance rates similar to those of calcium acetate and calcium carbonate. The most common adverse events after 52 weeks' treatment with sevelamer or a calcium-based phosphate binder in the largest study were GI in nature and included vomiting, nausea, diarrhoea and dyspepsia. Compared with calcium acetate alone, adverse events generally occurred at a similar rate with sevelamer in both short- and long-term studies. GI complaints, dyspepsia in particular, were significantly more common with sevelamer than with calcium carbonate after 52 weeks. Sevelamer was associated with clinically relevant reductions in serum bicarbonate levels in the minority of patients in the early stages of treatment, but produced clinically ‘safe’ final serum bicarbonate levels in the longer-term trials.