Renagel (Sevelamer Hydrochloride) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

Patients with end-stage renal disease (ESRD) 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 × 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. An increase in parathyroid hormone (PTH) levels is characteristic of patients with chronic renal failure. Increased levels of PTH can lead to osteitis fibrosa, a bone disease. A decrease in serum phosphorus may decrease serum PTH levels.

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 ESRD who are on hemodialysis. In vitro studies have shown that the capsule and tablet formulations bind phosphate to a similar extent. Renagel does not contain aluminum or other metals and does not cause aluminumintoxication.

Renagel treatment also results in a lowering of low-density lipoprotein (LDL) and total serum cholesterol levels.

Pharmacokinetics:    A mass balance study using¹⁴ C-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 trials:    The ability of Renagel Capsules to lower serum phosphorus in ESRD patients on hemodialysis 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). Two of the active-controlled studies are described here. One trial is a crossover trial with two 8-week periods comparing Renagel to calcium acetate and the other trial is a 52-week parallel design trial comparing Renagel tablets with calcium acetate and calcium carbonate.

Cross-over study of Renagel Capsules and calcium acetate: Eighty-four ESRD patients on hemodialysis who were hyperphosphatemic (serum phosphorus > 6.0 mg/dL) following a two-week phosphate binder washout period were randomized to receive either Renagel Capsules for eight weeks followed by calcium acetate for eight weeks or calcium acetate for eight weeks followed by Renagel Capsules for eight weeks. Treatment periods were separated by a two-week phosphate binder washout period. Patients started on Renagel Capsules or calcium acetate tablets three times per day with meals. Over each eight-week treatment period, at three separate time points the dose of either agent could be titrated up 1 capsule or tablet per meal (3 per day) to control serum phosphorus. Renagel Capsules and calcium acetate both significantly decreased mean serum phosphorus by about 2 mg/dL (Table 1).

Figure 1 illustrates that the proportion of patients achieving a given level of serum phosphorus lowering is comparable between the two treatment groups. For example, about half the patients in each group had a decrease of at least 2 mg/dL at endpoint.

Average daily consumption at the end of treatment was 4.9 g sevelamer hydrochloride (range of 0.0 to 12.6 g) and 5.0 g of calcium acetate (range of 0.0 to 17.8 g). During calcium acetate treatment, 22% of patients developed serum calcium >/= 11.0 mg/dL on at least one occasion versus 5% for Renagel (p < 0.05). Thus the risk of developing hypercalcemia is less with Renagel Capsules compared to calcium acetate.

Mean LDL cholesterol and mean total cholesterol declined significantly on Renagel Capsules treatment (-24% and -15%, respectively). Neither LDL nor total cholesterol changed on calcium acetate treatment. Triglycerides, high-density lipoprotein (HDL) cholesterol, and albumin did not change on either treatment.

Similar reductions in serum phosphorus and LDL cholesterol were observed in an eight-week open-label, uncontrolled study of 172 end stage renal disease patients on hemodialysis.

Parallel study of Renagel and calcium acetate or calcium carbonate:    Two hundred ESRD patients on hemodialysis who were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a two-week phosphate binder washout period were randomized to receive Renagel 800 mg tablets (N=99) or calcium, either calcium acetate (N=54) or calcium carbonate (N=47). Calcium acetate and calcium carbonate produced comparable decreases in serum phosphorus. At week 52, using last-observation-carried-forward, Renagel and Calcium both significantly decreased mean serum phosphorus (Table 2).

Sixty-one percent of Renagel patients and 73% of the calcium patients completed the full 52 weeks of treatment. The major reason for dropout in the Renagel group was gastrointestinal adverse events.

Figure 2, a plot of the phosphorus change from baseline for the completers, illustrates the durability of response for patients who are able to remain on treatment.

Average daily consumption at the end of treatment was 6.5 g of sevelamer hydrochloride (range of 0.8 to 13 g) or approximately eight 800 mg tablets (range of 1 to 16 tablets), 4.6 g of calcium acetate (range of 0.7 to 9.5 g) and 3.9 g of calcium carbonate (range 1.3 to 9.1 g). During calcium treatment, 34% of patients developed serum calcium corrected for albumin >/= 11.0 mg/dL on at least one occasion versus 7% for Renagel (p<0.05). Thus the risk of developing hypercalcemia is less with Renagel compared to calcium salts.

Mean LDL cholesterol and mean total cholesterol declined significantly (p<0.05) on Renagel treatment (-32% and -20%, respectively) compared to calcium (+0.2% and -2%, respectively). Triglycerides, HDL cholesterol, and albumin did not change.