Perfosen Mechanism of Action

Pharmacology: Mechanism of Action: Patients with chronic kidney disease (CKD) retain phosphorus and can develop hyperphosphatemia. 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 of intestinal phosphate absorption with phosphate binders, and removal of phosphate with dialysis. Sevelamer carbonate taken with meals has been shown to control serum phosphorus concentrations to patients with CKD who are on dialysis.
Pharmacodynamics: In addition to effects on serum phosphorus 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 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 adsorption 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.
Clinical efficacy and safety: In two randomized, cross over clinical trials, sevelamer carbonate in both tablet and powder formulations when administered three times per day has been shown to be therapeutically equivalent to sevelamer hydrochloride and therefore effective in controlling serum phosphorus in CKD patients on hemodialysis. 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 hemodialysis patients treated over two randomized 8-week treatment periods (mean serum phosphorus timeweighted 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 hyper phosphatemic (defined as serum phosphorus levels ≥1.78 mmol/l) hemodialysis patients over two randomized 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 hemodialysis patients, sevelamer alone did not have a consistent and clinically significant effect on 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 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 hypercalcemic 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.
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.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Rats were given sevelamer hydrochloride by diet at 0.3, 1, or 3 g/kg/day. There was an increased incidence of urinary bladder transitional cell papilloma in male rats of the high dose group (human equivalent dose twice the maximum clinical trial dose of 13 g). Mice received dietary administration of Sevelamer hydrochloride at doses of up to 9 g/kg/day (human equivalent dose 3 times the maximum clinical trial dose). There was no increased incidence of tumors observed in mice.
In an in vitro mammalian cytogenetic caused a statistically significant increase in the number of structural chromosome aberrations. Sevelamer hydrochloride was not mutagenic in the Ames bacterial mutation assay.
Sevelamer hydrochloride did not impair the fertility of male or female rats in a dietary administration study in which the females were treated from 14 days prior to mating through gestation and the males were treated for 28 days prior to mating.
Developmental Toxicity: In pregnant rats given dietary doses of 0.5, 1.5 or 4.5 g/kg/day of Sevelamer hydrochloride during organogenesis, reduced or irregular ossification of fetal bones, probably due to a reduced absorption of fat-soluble vitamin D, occurred in mid and high-dose groups (human equivalent doses approximately equal to 3-4 times the maximum clinical trial dose of 13 g). in pregnant rabbits given oral doses of 100, 500 or 1,000 mg/kg/day of Sevelamer hydrochloride by gavage during organogenesis, an increase of early resorptions occurred in the high-dose group.