CLINICAL PHARMACOLOGY
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.
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 test with metabolic activation, sevelamer
hydrochloride 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. The highest dose in this study was 4.5 g/kg/day (human equivalent
dose 3 times the maximum clinical trial dose of 13 g).
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 less than the
maximum clinical trial dose of 13 g). In pregnant rabbits given oral doses of 100,
500 or 1000 mg/kg/day of sevelamer hydrochloride by gavage during organogenesis,
an increase of early resorptions occurred in the high-dose group (human equivalent
dose twice the maximum clinical trial dose).
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