Colesevelam

The mechanism of action for the activity of colesevelam has been evaluated in several in vitro and in vivo studies. These studies have demonstrated that colesevelam binds bile acids, including glycocholic acid, the major bile acid in humans. Cholesterol is the sole precursor of bile acids. During normal digestion, bile acids are secreted into the intestine. A major portion of bile acids is then absorbed from the intestinal tract and returned to the liver via the enterohepatic circulation.

Colesevelam is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. The LDL-C lowering mechanism of bile acid sequestrants has been previously established as follows: As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effects of increasing transcription and activity of the cholesterol biosynthetic enzyme, hydroxymethyl-glutaryl-coenzyme A (HMG-CoA) reductase, and increasing the number of hepatic low-density lipoprotein receptors. A concomitant increase in very low density lipoprotein synthesis can occur. These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels.

Paediatric population

In the paediatric population, the safety and efficacy of 1.9 or 3.8 g/day colesevelam was assessed in an 8 week multi-centre, randomised, double-blind, placebo-controlled study in 194 boys and postmenarchal girls, aged 10-17 years, with heterozygous FH on a stable dose of statins (47 patients, 24%) or treatment-naïve to lipid-lowering therapy (147 patients, 76%). For all patients, colesevelam resulted in a statistically significant LDL-C reduction of 11% at 3.8 g/day and 4% at 1.9 g/day, versus a 3% increase in the placebo group. For statin-naïve patients on monotherapy, colesevelam resulted in a statistically significant LDL-C reduction of 12% at 3.8 g/day and 7% at 1.9 g/day, versus a 1% reduction in the placebo group. There were no significant effects on growth, sexual maturation, fat-soluble vitamin levels or clotting factors, and the adverse reaction profile for colesevelam was comparable to that seen with placebo.

Colesevelam has not been compared directly to other bile acid sequestrants in clinical trials.

So far, no studies have been conducted that directly demonstrate whether treatment with Colesevelam as monotherapy or combination therapy has any effect on cardiovascular morbidity or mortality.

Colesevelam is not absorbed from the gastrointestinal tract.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.