Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties
Pharmacotherapeutic group: All other therapeutic products, drugs for treatment of hyperkalemia and hyperphosphataemia. ATC code: V03A E02.

Mechanism of action

Renvela contains sevelamer, a non-absorbed phosphate binding crosslinked polymer, free of metal and calcium. Sevelamer contains multiple amines separated by one carbon from the polymer 
backbone which become protonated in the stomach. These protonated amines bind negatively charged ions such as dietary phosphate in the intestine.

Pharmacodynamic effects

By binding phosphate in the gastrointestinal tract and decreasing absorption, sevelamer lowers the phosphorus concentration in the serum. Regular monitoring of serum phosphorus levels is always necessary during phosphate binder administration.

Clinical efficacy and safety

In two randomised, cross over clinical trials, sevelamer carbonate has been shown to be therapeutically equivalent to sevelamer hydrochloride and therefore effective in controlling serum phosphorus in CKD patients on haemodialysis. These also demonstrated that sevelamer carbonate in both tablet and powder formulations are therapeutically equivalent to sevelamer hydrochloride.

The first study demonstrated that sevelamer carbonate tablets dosed three times per day was equivalent to sevelamer hydrochloride tablets dosed three times per day in 79 haemodialysis patients treated over two randomised 8 week treatment periods (mean serum phosphorus time-weighted averages were 1.5 ± 0.3 mmol/l for both sevelamer carbonate and sevelamer hydrochloride). The second study demonstrated that sevelamer carbonate powder dosed three times per day was equivalent to sevelamer hydrochloride tablets dosed three times per day in 31 hyperphosphataemic (defined as serum phosphorus levels ≥ 1.78 mmol/l) haemodialysis patients over two randomised 4 week treatment periods (mean serum phosphorus time-weighted averages were 1.6 ± 0.5 mmol/l for sevelamer carbonate powder and 1.7 ± 0.4 mmol/l for sevelamer hydrochloride tablets).

In the clinical trials in haemodialysis patients, sevelamer alone did not have a consistent and clinically significant effect on serum intact parathyroid hormone (iPTH). In a 12 week study involving peritoneal dialysis patients however, similar iPTH reductions were seen compared with patients receiving calcium acetate. In patients with secondary hyperparathyroidism sevelamer carbonate should be used within the context of a multiple therapeutic approach, which could include calcium as supplements, 1,25-dihydroxy Vitamin D3 or one of its analogues to lower the intact parathyroid hormone (iPTH) levels.

Sevelamer 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. In clinical trials of sevelamer, both the mean total-cholesterol and LDL-cholesterol declined by 15-39%.
The decrease in cholesterol has been observed after 2 weeks of treatment and is maintained with long-term treatment. Triglycerides, HDL-cholesterol and albumin levels did not change following sevelamer treatment.

Because sevelamer binds bile acids, it may interfere with the absorption of fat soluble vitamins such as A, D, E and K.

Sevelamer does not contain calcium and decreases the incidence of hypercalcaemic episodes as compared to patients using calcium based phosphate binders alone. The effects of sevelamer on phosphorus and calcium were proven to be maintained throughout a study with one year follow-up.
This information was obtained from studies in which sevelamer hydrochloride was used.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Pharmacokinetic studies have not been carried out with sevelamer carbonate. Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, is not absorbed from the gastrointestinal tract, as confirmed by an absorption study in healthy volunteers.

In a clinical trial of one year, no evidence of accumulation of sevelamer was seen. However the potential absorption and accumulation of sevelamer during long term chronic treatment (> one year) cannot be totally excluded.