Patients with chronic kidney disease (CKD) on dialysis retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum calcium resulting in ectopic calcification. When the product of serum calcium and phosphorus concentrations (Ca x P) exceeds 55 mg²/dL², there is an increased risk that ectopic calcification will occur. Hyperphosphatemia plays a role in the development of secondary hyperparathyroidism in renal insufficiency.

Treatment of hyperphosphatemia includes reduction in dietary intake of phosphate, inhibition of intestinal phosphate absorption with phosphate binders, and removal of phosphate with dialysis. Renagel taken with meals has been shown to decrease serum phosphorus concentrations in patients with CKD who are on dialysis.

Mechanism of Action

Renagel contains sevelamer hydrochloride, a non-absorbed binding crosslinked polymer. It contains multiple amines separated by one carbon from the polymer backbone. These amines exist in a protonated form in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the dietary tract and decreasing absorption, sevelamer hydrochloride lowers the phosphate concentration in the serum.

Pharmacodynamics

In addition to effects on serum phosphate levels, sevelamer hydrochloride has been shown to bind bile acids in vitro and in vivo in experimental animal models. Bile acid binding by ion exchange resins is a well-established method of lowering blood cholesterol. Because sevelamer binds bile acids, it may interfere with normal fat absorption and thus may reduce absorption of fat-soluble vitamins such as A, D and K. In clinical trials of sevelamer hydrochloride, both the mean total and LDL cholesterol declined by 15-31%. This effect is observed after 2 weeks. Triglycerides, HDL, cholesterol and albumin did not change.

Pharmacokinetics

A mass balance study using ¹⁴C-sevelamer hydrochloride in 16 healthy male and female volunteers showed that sevelamer hydrochloride is not systemically absorbed. No absorption studies have been performed in patients with renal disease.

Clinical Studies

The ability of Renagel to lower serum phosphorus in CKD patients on dialysis was demonstrated in six clinical trials: one double-blind placebo controlled 2-week study (Renagel N=24); two open-label uncontrolled 8-week studies (Renagel N=220) and three active-controlled open-label studies with treatment durations of 8 to 52 weeks (Renagel N=256). Three of the active-controlled studies are described here. One is a crossover study with two 8-week periods comparing Renagel to an active control. The second is a 52-week parallel study comparing Renagel with active control. The third is a 12-week parallel study comparing Renagel and active control in peritoneal dialysis patients.

Active-Control, Crossover Study in Hemodialysis Patients

Eighty-four CKD patients on hemodialysis who were hyperphosphatemic (serum phosphorus > 6.0 mg/dL) following a two-week phosphate binder washout period received Renagel and active control for eight weeks each in random order. Treatment periods were separated by a two-week phosphate binder washout period. Patients started on treatment three times per day with meals. Over each eight-week treatment period, at three separate time points the dose of Renagel could be titrated up 1 capsule or tablet per meal (3 per day) to control serum phosphorus, the dose of active control could also be altered to attain phosphate control. Both treatments significantly decreased mean serum phosphorus by about 2 mg/dL (Table 5).

Table 5. Mean Serum Phosphorus (mg/dL) at Baseline and Endpoint

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