Welchol Pharmacology, Pharmacokinetics, Studies, Metabolism - Colesevelam

Welchol Pharmacology, Pharmacokinetics, Studies, Metabolism - Colesevelam

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action for the lipid-lowering activity of colesevelam, the active pharmaceutical ingredient in WelChol™, has been evaluated in various 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 are 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. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-(alpha)-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 effect 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 (LDL) receptors. These compensatory effects result in increased clearance of LDL cholesterol (LDL-C) from the blood, resulting in decreased serum LDL-C levels. ^{1, 2}

Clinical studies have demonstrated that elevated levels of total cholesterol (total-C), LDL-C, and apolipoprotein B (Apo B, a protein associated with LDL-C) are associated with an increased risk of atherosclerosis in humans. Similarly, decreased levels of high-density lipoprotein cholesterol (HDL-C) are associated with the development of atherosclerosis ¹ . Epidemiological investigations have established that cardiovascular morbidity and mortality vary directly with the levels of total-C and LDL-C, and inversely with the level of HDL-C.

The combination of colesevelam and an HMG-CoA reductase inhibitor is effective in further lowering serum total-C and LDL-C levels beyond that achieved by either agent alone. The effects of colesevelam either alone or with an HMG-CoA reductase inhibitor on cardiovascular morbidity and mortality have not been determined.

Pharmacokinetics

Colesevelam is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed. In 16 healthy volunteers, an average of 0.05% of a single ¹⁴ C-labeled colesevelam dose was excreted in the urine when given following 28 days of chronic dosing of 1.9 grams of colesevelam twice per day.

Clinical Trials

WelChol™ reduces total-C, LDL-C, and Apo B, and increases HDL-C when administered either alone or in combination with an HMG-CoA reductase inhibitor in patients with primary hypercholesterolemia.

Approximately 1400 patients were studied in eight clinical trials with treatment durations ranging from 4 to 50 weeks. With the exception of one long-term study, all studies were multicenter, randomized, double-blind, and placebo-controlled. A maximum therapeutic response to WelChol™ was achieved within 2 weeks and was maintained during long-term therapy.

In a study in patients with LDL-C between 130 and 200 mg/dL (mean 158 mg/dL), WelChol™ was given for 24 weeks in divided doses with the morning and evening meals. As shown in Table 1 below, the mean LDL-C reductions were 15% and 18% at the 3.8 g and 4.5 g doses. The respective mean total-C reductions were 7% and 10%. The mean Apo B reductions were 12% in both treatment groups. WelChol™ at both doses increased HDL-C by 3%. There were small increases in triglycerides (TG) at both WelChol™ doses that were not statistically different from placebo.

In a study in 98 patients with LDL-C between 145 and 250 mg/dL (mean 169 mg/dL), WelChol™ 3.8 g was given for 6 weeks as a single dose with breakfast, a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the three dosing regimens, respectively. The reductions with these three regimens were not statistically different from one another.

Co-administration of WelChol™ and an HMG-CoA reductase inhibitor (atorvastatin, lovastatin, or simvastatin) demonstrated an additive reduction of LDL-C in three clinical studies. As demonstrated in Table 2 below, WelChol™ doses of 2.3 g to 3.8 g resulted in additional 8% to 16% reductions in LDL-C above that seen with the HMG-CoA reductase inhibitor alone.

In all three studies, the LDL-C reduction achieved with the combination of WelChol™ and any given doses of HMG-CoA reductase inhibitor therapy was statistically superior to that achieved with WelChol™ or that dose of the HMG-CoA reductase inhibitor alone.

The LDL-C reduction with atorvastatin 80 mg was not statistically significantly different from the combination of WelChol™ 3.8 g and atorvastatin 10 mg.