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PubMedDate not supplied

Colesevelam hydrochloride: a novel bile acid-binding resin.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of colesevelam hydrochloride, a bile acid-binding resin. METHODS: MEDLINE searches (1966-June 2000) and manufacturer prescribing literature were employed to find articles on colesevelam. Additional studies and abstracts were identified from the bibliographies of reviewed literature. STUDY SELECTION AND DATA EXTRACTION: All articles identified from data sources were evaluated, and all information deemed relevant was included in this review. Priority was given to randomized, double-blind, placebo-controlled studies. FINDINGS: Colesevelam HCl is a nonabsorbed hydrogel with bile acid sequestrant properties. Monotherapy using colesevelam in once-daily or two divided daily doses of 1.5-4.5 g has produced significant reductions in total cholesterol and low-density lipoprotein (LDL) cholesterol. Mean LDL cholesterol decreases to 20% have been noted when the patient is on 3.75-4.5 g/d. Increases in high-density lipoprotein (HDL) cholesterol have been observed (up to 9%), whereas triglycerides (TG) have increased significantly to 25% in some studies. In unpublished studies, combined use of colesevelam plus hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor have produced greater reductions in LDL cholesterol than either the statin or colesevelam administered alone. The efficacy of colesevelam monotherapy is slightly less than or similar to cholestyramine or colestipol in decreasing LDL cholesterol, although colesevelam is more potent on a gram-to-gram basis. Adverse effects have been minimal with colesevelam in published studies; this suggests an advantage over cholestyramine or colestipol therapy. Colesevelam appears to be more cost-effective than the packet dosage form of the brand formulation of the older bile acid resins. Care in selection of an appropriate agent should be exercised when considering the issues of adverse effects and palatability. CONCLUSIONS: Colesevelam alone or combined with an HMG-CoA reductase inhibitor is effective in the reduction of total and LDL cholesterol. Since colesevelam is formulated as a tablet, problems with palatability such as with the powder formulation of the bile acid-binding resins are likely to be eliminated.

Adult↗

PubMed2002

Colesevelam hydrochloride.

The pharmacology, pharmacodynamics, clinical efficacy, drug interactions, adverse effects, and dosage and administration of colesevelam hydrochloride are reviewed. Colesevelam hydrochloride is a nonabsorbed lipid-lowering agent approved for use alone or in combination with hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors for the reduction of low-density-lipoprotein (LDL) cholesterol in patients with primary hypercholesterolemia. Colesevelam forms nonabsorbable complexes with bile acids in the gastrointestinal (GI) tract, resulting in changes in plasma lipid levels, including total, LDL, and high-density-lipoprotein cholesterol and triglycerides. Colesevelam has been reported to be four to six times as potent as traditional bile acid sequestrants (BASs), perhaps because of its greater binding affinity for glycocholic acid. Unlike cholestyramine and colestipol, colesevelam appears to reduce LDL cholesterol in a dose-dependent manner. In clinical trials, colesevelam demonstrated efficacy either alone or in combination with HMG-CoA reductase inhibitors in the treatment of primary hypercholesterolemia. Combination therapy appeared to be more effective than monotherapy. Although infection, headache, and GI adverse effects have been reported for colesevelam, the rates do not differ significantly from those occurring with placebo. The constipation that typically hinders compliance with traditional BASs is minimal. In one study, the rate of compliance with colesevelam was 93%. There is little evidence of clinically significant interactions involving colesevelam. The maintenance dosage is three 625-mg tablets twice daily or six tablets once daily, taken with meals. Colesevelam provides an effective alternative to cholestyramine and colestipol while offering the potential for fewer adverse effects and better compliance. Studies are needed to directly compare colesevelam with traditional BASs.

Allylamine↗

PubMed2002

Absorption of colesevelam hydrochloride in healthy volunteers.

OBJECTIVE: To assess whether colesevelam hydrochloride is absorbed in healthy volunteers. METHODS: A single-center, open-label, radiolabeled study was performed with 16 healthy volunteers. Subjects were administered non-radiolabeled colesevelam hydrochloride 1.9 g twice daily for 4 weeks, followed by a single dose of [14C]-colesevelam 2.4 g (480 pCi). These subjects continued to receive non-radioactive colesevelam 1.9 g twice daily for 4 days after administration of the radiolabeled dose. Blood, urine, and feces were collected immediately prior to administration of [14C]-colesevelam and at specified intervals after administration. The whole-blood equivalent concentration of colesevelam was calculated using data collected throughout the 96 hours following radiolabeled drug administration. The proportion of [14C]-colesevelam excreted through urine or feces was calculated based on the amount of radioactivity recovered up to 216 hours after the radiolabeled dose. RESULTS: The mean cumulative total recovery of [14C]-colesevelam in urine and feces was 0.05% and 74%, respectively. Excluding 2 subjects for whom cumulative recovery was <25%, the mean cumulative fecal recovery was 82%. The mean maximum whole-blood equivalent concentration of colesevelam was 0.165+/-0.10 microg equiv/g 72 hours after administration of [14C]-colesevelam, which was estimated to be 0.04% of the administered dose. All blood samples contained <4 times the number of background counts (dpm). CONCLUSIONS: The cumulative recovery data in urine and feces are consistent with the conclusion that colesevelam is not absorbed and is excreted entirely through the gastrointestinal system.

Allylamine↗

PubMed2001

Low-dose combination therapy with colesevelam hydrochloride and lovastatin effectively decreases low-density lipoprotein cholesterol in patients with primary hypercholesterolemia.

BACKGROUND: Colesevelam hydrochloride is a novel, lipid-lowering agent that binds bile acids with high affinity. A multicenter, randomized, double-blind, placebo-controlled, parallel-design study was conducted to assess the efficacy and tolerability of combination low-dose colesevelam and lovastatin treatment in patients with primary hypercholesterolemia. HYPOTHESIS: Combination therapy with low doses of colesevelam and lovastatin decreases low density (LDL) cholesterol with minimal adverse events. METHODS: Following a 4- to 6-week dietary lead in, 135 patients were randomized into five groups for a 4-week treatment period: placebo, colesevelam 2.3 g at dinner, lovastatin 10 mg at dinner, the combination of colesevelam and lovastatin given at dinner (dosed together), and combination treatment with colesevelam given at dinner and lovastatin administered at bedtime (dosed apart). RESULTS: Combination colesevelam and lovastatin treatment decreased LDL cholesterol by 34% (60 mg/dl, p < 0.0001) and 32% (53 mg/dl, p < 0.0001) when colesevelam and lovastatin were dosed together or dosed apart, respectively. Both combination therapies were superior to either agent alone (p < 0.05). Decreases in LDL cholesterol exceeded the combined decreases observed for colesevelam alone (13 mg/dl, 7%) and lovastatin alone (39 mg/dl, 22%). Both combination treatments reduced total cholesterol by 21% (p < 0.0001) and apolipoprotein B by 24% (p < 0.0001). Neither combination treatment significantly altered high-density lipoprotein cholesterol or triglycerides. Adverse side effects were not significantly different among randomized groups. CONCLUSIONS: Combination colesevelam and lovastatin was efficacious and well tolerated, resulting in additive decreases in LDL cholesterol levels whether or not both agents were administered simultaneously.

Allylamine↗

PubMed2025

The Effect of Colesevelam on the Microbiome in Postoperative Crohn's Disease.

BACKGROUND: While surgery plays a pivotal role in the management of ileal Crohn's disease, the risk of endoscopic recurrence following an ileocaecal resection can be greater than 65% within 12 months of surgery. More than 90% of patients with Crohn's disease have a concomitant diagnosis of bile acid diarrhea following an ileal resection. This pilot study aimed to assess whether the use of bile acid sequestrants in patients with Crohn's disease who have undergone a primary terminal ileal resection with concomitant bile acid diarrhea can alter the microbiome and prevent disease recurrence. METHODS: Patients with Crohn's disease who underwent a primary terminal ileal resection and had symptoms of diarrhea within 1-3 months of surgery underwent 75SeHCAT testing for bile acid diarrhea. If positive (75SeHCAT ≤ 15%), patients were treated with colesevelam and stool samples were collected at 4 weeks, 8 weeks, and 6-12 months posttreatment. If negative (75SeHCAT > 15%), treatment was not given and were reviewed in the clinic as per local guidelines. All patients underwent a 6-12 month postoperative colonoscopy where further stool samples and mucosal biopsies were taken. Disease activity was established using the endoscopic Rutgeert's score, with disease remission defined as Rutgeert's score <i2 and disease recurrence ≥i2. 16S ribosomal RNA gene analysis was undertaken for the collected fecal and mucosal samples to assess α/β-diversity and microbial composition. RESULTS: A total of 14 patients who completed the study, 10 of whom had a 75SeHCAT positive diagnosis of bile acid diarrhea and were started on treatment with colesevelam. Four patients did not require treatment as 3 were asymptomatic and 1 had a negative 75SeHCAT scan. Three of the fourteen patients had disease recurrence at their 6-12 month postoperative colonoscopy assessment, of which 1 patient was taking colesevelam and 2 patients were not taking colesevelam. A total of 44 fecal samples and 44 mucosal biopsies underwent 16S ribosomal RNA gene analysis to assess α/β-diversity and microbial composition. In the colesevelam treated patients there was no significant difference in α/β-diversity pre- and posttreatment. Pretreatment, the 3 most abundant bacterial classes in all patients were Bacteroidia, Clostridia, and Gammaproteobacteria. Following 6-12 months of treatment, out of the 9 patients on colesevelam, 5/9 (55.6%) had a reduction in Bacteroidia, 9/9 (100%) had an increase in Clostridia, and 7/9 (77.8%) had a reduction in Gammaproteobacteria. Of the 2 patients not given colesevelam, one showed a reduction in Bacteroidia, increase in Clostridia and a reduction in Gammaproteobacteria. CONCLUSIONS: This small pilot study demonstrated that patients who were given colesevelam, were more likely to be in disease remission at their 6-12 months colonoscopy review compared with those not treated. Furthermore, treatment with colesevelam may have a role in altering the microbiome to help maintain remission states in postoperative Crohn's disease. Larger mechanistic studies are now needed to confirm these findings and demonstrate statistical significance as well as investigate whether this benefit may be present even in those patients with 75SeHCAT negative disease.

Humans↗

PubMed2004

Effect of colesevelam HCl on single-dose fenofibrate pharmacokinetics.

OBJECTIVE: The primary aim of this study was to determine whether there is an effect of colesevelam HCl (WelChol; Sankyo Pharma Inc., Parsippany, NJ, USA) on fenofibric acid (active metabolite of fenofibrate, TriCor, Abbott Laboratories, North Chicago, IL, USA) pharmacokinetics following single-dose fenofibrate when colesevelam HCl and fenofibrate are administered concomitantly, or when colesevelam HCl is administered 4 hours following fenofibrate therapy. METHODS: Thirty healthy volunteers were enrolled in a randomised, open-label, three-way crossover, drug interaction study. Subjects received one of three treatments at each of three dose administration periods: (i) treatment A -- fenofibrate 160 mg plus colesevelam HCl 3750 mg (6 x 625 mg tablets) administered with breakfast; (ii) treatment B -- fenofibrate 160 mg administered with breakfast, followed 4 hours later by colesevelam HCl 3750 mg (6 x 625 mg tablets) administered with lunch; or (iii) treatment C -- fenofibrate 160 mg administered with breakfast. Treatments were separated by a 10-day washout period. Blood samples were collected at predetermined time intervals, both before and after drug administration. Plasma concentrations of fenofibrate and fenofibric acid were measured using a validated liquid chromatography/mass spectroscopy/mass spectroscopy method. RESULTS: Area under the concentration-time curve (AUC) from time zero to the timepoint of the lowest quantifiable concentration (AUCt), AUC from time zero to infinity (AUCinfinity) and maximum plasma concentration (Cmax) for fenofibric acid were 92.1%, 93.9% and 79.8%, respectively, of control values when colesevelam HCl and fenofibrate were coadministered with breakfast; and 91.9%, 93.9% and 99.1%, respectively, when fenofibrate was administered followed 4 hours later by administration of colesevelam HCl. The 90% confidence intervals for the ratios of geometric means for AUCt, AUCinfinity and Cmax comparing the three treatments were contained within the 80-125% equivalence range, with the exception of Cmax for treatment A. Coadministration of fenofibrate with colesevelam HCl resulted in an approximate 20% reduction in Cmax of the active metabolite (fenofibric acid). There were no significant differences in the time to Cmax, elimination rate constant or elimination half-life between any of the treatment groups. CONCLUSIONS: Colesevelam HCl had no significant effect on fenofibrate bioavailability when administered either concomitantly with fenofibrate or 4 hours after fenofibrate.

Adult↗

PubMed1999

Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects.

OBJECTIVES: To compare colesevelam hydrochloride (Cholestagel), a nonabsorbed hydrogel with bile acid-sequestering properties, with placebo for its lipid-lowering efficacy, its effects on laboratory and clinical safety parameters, and the incidence of adverse events. METHODS: Following diet and placebo lead-in periods, placebo or colesevelam was administered at 4 dosages (1.5, 2.25, 3.0, or 3.75 g/d) for 6 weeks with morning and evening meals to men and women with hypercholesterolemia (low-density lipoprotein cholesterol level >4.14 mmol/L [>160 mg/dL]). Patients returned to the clinic every 2 weeks throughout the treatment period for lipid parameter measurements and adverse event assessments. Samples were collected for serum chemistry profiles, hematologic studies, coagulation studies, and vitamin level assessment at baseline and after 6 weeks of treatment. RESULTS: Among the 149 patients randomized, 137 completed the study. Low-density lipoprotein cholesterol concentrations decreased in a dosage-dependent manner by 0.11 mmol/L (4.2 mg/dL) (1.8%) in the 1.5-g/d colesevelam treatment group and up to 1.01 mmol/L (39 mg/dL) (19.1%) in the 3.75-g/d colesevelam treatment group. Low-density lipoprotein cholesterol concentrations at the end of treatment were significantly reduced from baseline levels in the 3.0- and 3.75-g/d colesevelam treatment groups (P = .01 and P<.001, respectively). Total cholesterol levels demonstrated a similar response to colesevelam treatment, with an 8. 1% decrease from baseline in the 3.75-g/d treatment group (P<.001). High-density lipoprotein cholesterol levels rose significantly in the 3.0- and 3.75-g/d colesevelam treatment groups, by 11.2% (P=.006) and 8.1% (P=.02), respectively. Median triglyceride levels did not change from baseline, nor were there any significant differences between treatment groups. The incidence of adverse events was similar among all groups. CONCLUSIONS: Colesevelam therapy is effective for lowering low-density lipoprotein cholesterol concentrations in persons with moderate hypercholesterolemia. It lacks the constipating effect of other bile acid sequestrants, demonstrating the potential for increased compliance.

Adult↗

PubMed2000

Colesevelam hydrochloride: a non-absorbed, polymeric cholesterol-lowering agent.

Colesevelam hydrochloride (formerly known as Cholestagel((R)) and re-named WelCholtrade mark, GelTex Pharmaceuticals, Inc. and Sankyo Parke-Davis) is a new, polymeric, high potency, water-absorbing hydrogel. It has been shown to be a safe and effective cholesterol-lowering agent with a non-systemic mechanism of action, good tolerability and minimal side effects. To date, the lipid-lowering activity of colesevelam has been evaluated in approximately 1400 subjects. Colesevelam reduces low density lipoprotein (LDL)-cholesterol levels, in a dose-dependent manner, by as much as 20% (median) in patients with hypercholesterolaemia. Dosing regimen evaluations indicate that colesevelam is effective at both once per day and twice daily dosing and that concurrent administration of colesevelam with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), specifically lovastatin, does not alter the absorption of the statin. Combination therapy with HMG-CoA reductase inhibitors, including lovastatin, simvastatin and atorvastatin, produces an additional reduction (8 - 16%) in LDL-cholesterol levels above that seen with the statin alone. The overall incidence of adverse effects with colesevelam alone and in combination with statins is comparable with that seen with placebo. Colesevelam lacks the constipating effect seen with typical bile acid sequestrants, a trait that would be expected to improve compliance with lipid-lowering therapy. Colesevelam, recently approved by the US FDA, represents a valuable non-absorbed alternative in the armamentarium against hypercholesterolaemia, both for monotherapy and combination therapy, as an adjunct to diet and exercise.

Allylamine↗

PubMed2006

Effects of colesevelam hydrochloride on low-density lipoprotein cholesterol and high-sensitivity C-reactive protein when added to statins in patients with hypercholesterolemia.

Elevated high-sensitivity C-reactive protein (hs-CRP) levels are associated with an increased risk of atherosclerotic coronary heart disease (CHD). The addition of the bile acid sequestrants, such as colesevelam hydrochloride (HCl), to statins further reduces low-density lipoprotein (LDL) cholesterol levels. However, the effects of approved cholesterol-lowering bile acid sequestrants on hs-CRP have not previously been reported. Three randomized, double-blind, placebo-controlled, parallel, 6-week clinical trials of similar design investigated the efficacy of adding colesevelam HCl to stable simvastatin, atorvastatin, or pravastatin treatment in 204 patients with primary hypercholesterolemia. The primary end point was the mean percent change in the LDL cholesterol levels. Secondary end points included the effects on other lipid parameters and hs-CRP levels. A pooled analysis showed that adding colesevelam HCl to statin therapy significantly lowered LDL cholesterol levels (21 mg/dl or 16% mean reduction from baseline, p = 0.0013, and 11 mg/dl or 9% mean reduction compared with placebo, p = 0.0003). Four times as many patients receiving colesevelam HCl plus a statin achieved a LDL cholesterol target of <100 mg/dl compared with patients receiving a statin plus placebo (39% vs 10%, respectively, p <0.0001). The incidence of mild gastrointestinal adverse effects was slightly higher in the colesevelam HCl plus statin group than in the placebo plus statin group. Finally, the differences in the change in hs-CRP levels with colesevelam HCl plus statin therapy were significant compared with the changes with placebo plus statin (median change -23%, p = 0.0069). In conclusion, this is the first report suggesting that an approved cholesterol-lowering bile acid sequestrant, specifically colesevelam HCl, decreases hs-CRP levels when added to statin therapy.

Allylamine↗

PubMed2006

Effects of colesevelam hydrochloride (WelChol) on biomarkers of inflammation in patients with mild hypercholesterolemia.

Inflammation is pivotal in atherogenesis. High-sensitivity C-reactive protein (hs-CRP), the prototypic marker of inflammation, has been shown to predict cardiovascular events. Colesevelam hydrochloride (HCl) (WelChol, Sankyo Pharma Incorporated, Parsippany, New Jersey), a specifically engineered bile acid sequestrant, has been shown to be effective in lowering low-density lipoprotein (LDL) cholesterol levels in monotherapy and in combination with statins or fenofibrate. Previously, we have shown that statins lower hs-CRP levels; however, a paucity of data is available examining the effect of colesevelam HCl on hs-CRP levels. The aim of this study was to examine the effect of colesevelam HCl therapy (3.75 g/day for 6 weeks) on hs-CRP in patients with mild hypercholesterolemia in a randomized, double-blind, placebo-controlled study. Twenty-five subjects on colesevelam HCl and 23 subjects on placebo completed the study. The median baseline hs-CRP levels for the treatment and placebo groups are 3.4 and 3.1 mg/L, respectively. Colesevelam HCl therapy resulted in a significant reduction in LDL cholesterol levels (p < 0.001). No significant changes were found in total triglyceride or high-density lipoprotein cholesterol levels between the 2 groups. Furthermore, colesevelam HCl therapy resulted in a significant reduction in hs-CRP levels compared with baseline and placebo (15.9% and 18.7% median reduction, respectively, p < 0.025). No correlation was found between LDL cholesterol lowering and hs-CRP lowering (r = 0.3). In conclusion, our results show that colesevelam HCl monotherapy significantly lowered hs-CRP levels in a double-blind, placebo-controlled study.

Adult↗

PubMed2005

Colesevelam hydrochloride does not cause maternal or fetal toxicity in rats and rabbits.

WelChol (colesevelam hydrochloride), a bile acid sequestrant for the treatment of hypercholesterolemia, was evaluated for adverse effects on reproduction and fetal development using standard preclinical tests. During gestation, Sprague-Dawley rats used in the developmental toxicity study received feed, feed/control article or feed plus 300, 1,000 or 3,000 mg/kg/day colesevelam whereas rats in the pre- and postnatal toxicity study received vehicle or 100, 300 or 1,000 mg/kg/day colesevelam via gavage. New Zealand white rabbits received control or 100, 500 or 1,000 mg/kg/day colesevelam via gavage. No deaths, premature deliveries or gross pathologic lesions were observed up to gestation day (GD) 20 for rats and GD 28 for rabbits. No significant differences in the number of pregnant animals, average litter size, percentage of viable fetuses, fetal body weights, number of corpora lutea, fetal viability, or gross malformations were observed versus controls. Pre- and postnatal effects were assessed in pregnant rats receiving 100, 300 or 1,000 mg/kg/day colesevelam from GD 6 to postpartum day 22. Gestation, parturition and lactation in F(0) generation dams were similar between treatment and control groups. Colesevelam did not affect physical or neurological development or induce gross pathological changes in F(1) generation rats. Colesevelam does not produce developmental toxicity in rats or rabbits, nor does it exhibit pre- or postnatal toxicity in rats at the tested doses.

Allylamine↗

PubMed2001

Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia.

PURPOSE: To examine the efficacy and safety of colesevelam hydrochloride, a novel, nonsystemic, lipid-lowering agent, when coadministered with starting doses of simvastatin in a multicenter, randomized, double-blind, placebo-controlled trial. PATIENTS AND METHODS: Subjects with hypercholesterolemia (plasma low density lipoprotein [LDL] cholesterol level > 160 mg/dL and triglyceride level < or = 300 mg/dL) were randomly assigned to receive daily doses of placebo (n = 33), colesevelam 3.8 g (recommended dose, n = 37), simvastatin 10 mg (n = 35), colesevelam 3.8 g with simvastatin 10 mg (n = 34), colesevelam 2.3 g (low dose, n = 36), simvastatin 20 mg (n = 39), or colesevelam 2.3 g with simvastatin 20 mg (n = 37), for 6 weeks. RESULTS: Mean LDL cholesterol levels decreased relative to baseline in the placebo group (P < 0.05) and in all active treatment groups (P < 0.0001). For groups treated with combination therapy, the mean reduction in LDL cholesterol level was 42% (-80 mg/dL; P < 0.0001 compared with baseline), which exceeded the reductions for simvastatin 10 mg (-26%, -48 mg/dL) or 20 mg (-34%, -61 mg/dL) alone, or for colesevelam 2.3 g (-8%, -17 mg/dL) or 3.8 g (-16%, -31 mg/dL) alone (P < 0.001). The effects of combination therapy on serum HDL cholesterol and triglyceride levels were similar to those for simvastatin alone. Side effects were similar among treatment groups, and there were no clinically important changes in laboratory parameters. CONCLUSION: Coadministration of colesevelam and simvastatin was effective and well tolerated, providing additive reductions in LDL cholesterol levels compared with either agent alone.

Adult↗

PubMed2001

Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively.

Colesevelam hydrochloride is a novel, potent, non-absorbed lipid-lowering agent previously shown to reduce low density lipoprotein (LDL) cholesterol. To examine the efficacy and safety of coadministration of colesevelam and atorvastatin, administration of these agents alone or in combination was examined in a double-blind study of 94 hypercholesterolemic men and women (baseline LDL cholesterol > or =160 mg/dl). After 4 weeks on the American Heart Association Step I diet, patients were randomized among five groups: placebo; colesevelam 3.8 g/day; atorvastatin 10 mg/day; coadminstered colesevelam 3.8 g/day plus atorvastatin 10 mg/day; or atorvastatin 80 mg/day. Fasting lipids were measured at screening, baseline and 2 and 4 weeks of treatment. LDL cholesterol decreased by 12-53% in all active treatment groups (P<0.01). LDL cholesterol reductions with combination therapy (48%) were statistically superior to colesevelam (12%) or low-dose atorvastatin (38%) alone (P<0.01), but similar to those achieved with atorvastatin 80 mg/day (53%). Total cholesterol decreased 6-39% in all active treatment groups (P<0.05). High density lipoprotein cholesterol increased significantly for all groups including placebo (P<0.05). Triglycerides decreased in patients taking atorvastatin alone (P<0.05), but were unaffected by colesevelam alone or in combination. The frequency of side effects did not differ among groups. At recommended starting doses of each agent, coadministration of colesevelam and atorvastatin was well tolerated, efficacious and produced additive LDL cholesterol reductions comparable to those observed with the maximum atorvastatin dose.

Adult↗

PubMed2000

Drug interactions with colesevelam hydrochloride, a novel, potent lipid-lowering agent.

Colesevelam hydrochloride (colesevelam) is a novel, potent, bile acid-binding agent that has been shown to lower LDL cholesterol a mean of 19% at a dose of 3.8 g/d. We studied the pharmacokinetics of colesevelam coadministered with six drugs: digoxin and warfarin, agents with narrow therapeutic indices; sustained-release verapamil and metoprolol; quinidine, an antiarrhythmic with a narrow therapeutic index; and valproic acid, an antiseizure medication. Six individual studies were single-dose, crossover, with or without a 4.5-g dose of colesevelam. Plasma levels were determined using validated analytical methods. Values for the ratio of ln[AUC(0-t)] with and without colesevelam were 107% for quinidine, 102% for valproic acid, 89% for digoxin, 102% for warfarin, 82% for verapamil, and 112% for metoprolol. Values for the ratio of ln[Cmax] with and without colesevelam were 107% for quinidine, 92% for valproic acid, 96% for digoxin, 99% for warfarin, 69% for verapamil, and 112% for metoprolol. The 90% confidence intervals for these ratios and for values of ln[AUC(0-inf)] that could be determined were within the 80-125% range, with the exception of verapamil. In this study, verapamil had great interindividual variability, with a 28-fold range in Cmax and an 11-fold range in AUC(0-t). In summary, pharmacokinetic studies with colesevelam did not show clinically significant effects on absorption of six other coadministered drugs.

Allylamine↗

PubMedDate not supplied

Dietary administration of colesevelam hydrochloride does not affect fertility or reproductive performance in rats.

Colesevelam hydrochloride (HCl) (WelChol; Sankyo Pharma) is a novel, highly potent, bile acid-binding polymer used for the treatment of hypercholesterolemia. The primary aim of this study was to determine the effects of dietarily administered colesevelam HCl on fertility and reproductive performance parameters. To assess these effects, sexually mature Sprague-Dawley rats were randomized to one of five treatment groups: feed alone, feed plus control article (SigmaCell), or feed plus colesevelam HCl 200, 1000, or 2000 mg/kg/day. Male and female rats were administered the appropriate group agent for 28 and 15 days, respectively, and were subsequently paired together for cohabitation and mating. Females continued to receive the test agent in their dietary formulation through presumed gestation day (GD) 7. Presumed pregnant females underwent cesarean section on GD 20. Food consumption rate, body weight, gross necropsy, and standard preclinical tests for reproduction and fertility were performed for each test animal. No statistically significant differences were found between control and drug-treated groups for any tested endpoints of reproduction. All animals placed in cohabitation successfully mated. Uterine and litter end points were unaffected by dosages of colesevelam HCl as high as 2000 mg/kg/day. There were no significant differences between treatment group litter averages in the number of corpora lutea, implantation sites, litter size, live fetuses, body weights, early/late resorptions, and the number of dams with viable fetuses. In addition, no external alterations of fetal morphology were attributable to treatment with colesevelam HCl when administered up to the embryo implantation stage. In male animals, no significant differences were found between the colesevelam HCl and control study groups in the average caudal epididymal sperm count or sperm concentration, total number of motile and nonmotile sperm, and the total percentage of motile sperm. Based on these data, colesevelam HCl does not have any significant adverse reproductive or fertility effects in rats, even when administered at doses approximately 30 times greater than the approved clinical dose.

Administration, Oral↗

PubMed2005

Colesevelam: potential uses for the newest bile resin.

Colesevelam is the newest bile resin with a unique chemical structure. It binds to bile acids with higher affinity than traditional bile acid sequestrants and has fewer gastrointestinal side effects and drug interactions. Colesevelam is safe and efficacious alone or in combination with HMG-CoA reductase inhibitors (statins) in reducing low-density lipoprotein cholesterol (LDL-C) levels. Despite this, the role of colesevelam in the treatment of hyperlipidemia remains limited, particularly in the face of new lipid lowering agents. As guidelines for cholesterol control become more stringent, the need to maximize therapeutic benefit through combination therapy will become increasingly more important. Colesevelam has a dose-sparing effect on statin therapy, potentially decreasing the risk of unwanted side effects or drug-drug interactions associated with statin use. This makes colesevelam a viable option for addition to a statin regimen when goal LDL-C levels cannot be achieved with a statin alone. Additionally, anecdotal reports indicate that colesevelam may have potential benefits in certain patient populations that cannot tolerate other lipid lowering therapies, including organ transplant recipients, cholestatic liver disesase, and end-stage renal disease. By recognizing the potential utility of colesevelam, clinicians can better manage those patients who are not able to tolerate first-line therapies.

Allylamine↗

PubMed2006

Lipid-lowering effects of colesevelam HCl in combination with ezetimibe.

OBJECTIVE: The primary aim of this study was to compare the effect of colesevelam HCl in combination with ezetimibe to ezetimibe monotherapy on low-density lipoprotein cholesterol (LDL-C) levels in subjects with primary hypercholesterolemia. METHODS: Subjects with primary hypercholesterolemia (N = 86) were enrolled in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. After a 4- to 8-week washout period, subjects received colesevelam HCl 3.8 g/day plus ezetimibe 10 mg/day or colesevelam HCl placebo plus ezetimibe 10 mg/day for 6 weeks. The primary efficacy endpoint was the mean percent change in LDL-C during randomized treatment. Secondary endpoints included mean absolute change in LDL-C, mean absolute and mean percent change in levels of high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC), apolipoprotein (apo) A-I and apo B, and median absolute and percent changes in triglycerides (TG) and high-sensitivity C-reactive protein from baseline to end of treatment. Of the 86 subjects randomized to treatment, 85 were included in the intent-to-treat analysis. RESULTS: After 6 weeks of treatment, colesevelam HCl plus ezetimibe produced a mean percent change in LDL-C of -32.3% versus -21.4% with ezetimibe monotherapy (p < 0.0001). Colesevelam HCl plus ezetimibe was significantly more effective than ezetimibe alone at producing mean percent reductions in TC, non-HDL-C, and apo B and increases in apo A-I (p < 0.005 for all). Neither treatment regimen resulted in significant changes in median TG levels compared with baseline (p = NS). Both treatments were safe and generally well tolerated. CONCLUSIONS: Colesevelam HCl plus ezetimibe combination therapy significantly reduced mean LDL-C, TC, non-HDL-C, and apo B levels and increased apo A-I levels (p < 0.005 for all) without significantly increasing median TG levels in hypercholesterolemic subjects compared with ezetimibe alone. Although limited in that atherosclerotic coronary heart disease outcomes were not evaluated, this study demonstrated that combining colesevelam HCl with ezetimibe is a therapeutic option in hypercholesterolemic patients, such as those in whom statins are contraindicated and/or who may have intolerances to statin therapy.

Adult↗

PubMed2001

Colesevelam.

Colesevelam, a bile acid sequestrant used in the treatment of patients with hypercholesterolemia, is a lipid-lowering polymer that has high affinity for bile acids. In animals colesevelam was not systemically absorbed after oral administration and was rapidly eliminated via the gastrointestinal tract. Colesevelam did not alter the serum concentrations or pharmacokinetic properties of drugs from several different classes in healthy volunteers. Colesevelam administered orally in patients with primary hypercholesterolemia significantly reduced serum levels of low density lipoprotein (LDL)-cholesterol and total cholesterol. This lipid-lowering activity was sustained during short (6 weeks) and longer term (24 weeks) treatment. Combination therapy with colesevelam plus hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (lovastatin, simvastatin or atorvastatin) was associated with additive reductions in serum levels of LDL-cholesterol and total cholesterol, relative to either agent alone. Colesevelam treatment was well tolerated and lacked severe gastrointestinal adverse events typical of other bile acid sequestrants (bloating, flatulence, heartburn and nausea). The most frequently reported adverse events were constipation and dyspepsia. In humans colesevelam did not induce clinically significant changes in serum levels of vitamins, coagulation parameters or liver enzymes.

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