Actions of Colesvir in details
Colesvir is structurally similar to the HMG, a substituent of the endogenous substrate of HMG-CoA reductase. Colesvir is a prodrug that is activated in vivo via hydrolysis of the lactone ring to form the β-hydroxyacid. The hydrolyzed lactone ring mimics the tetrahedral intermediate produced by the reductase allowing the agent to bind to HMG-CoA reductase with 20,000 times greater affinity than its natural substrate. The bicyclic portion of Colesvir binds to the coenzyme A portion of the active site.
How should I take Colesvir?
Take Colesvir exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label.
Take Colesvir with a full glass of water. Do not crush, chew, or break an extended-release tablet. Swallow the pill whole. It is specially made to release medicine slowly in the body. Breaking or opening the pill would cause too much of the drug to be released at one time. Colesvir is usually taken at bedtime or with an evening meal. If you take Colesvir several times daily, take it with meals. Follow your doctor's instructions.
To be sure this medication is helping your condition, your blood will need to be tested on a regular basis. Your liver function may also need to be tested. Do not miss any scheduled appointments.
In rare cases, Colesvir can cause a condition that results in the breakdown of skeletal muscle tissue. This condition can lead to kidney failure. Call your doctor at once if you have unexplained muscle pain or tenderness, muscle weakness, fever or flu symptoms, and dark colored urine.
Colesvir is only part of a complete program of treatment that also includes diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely.
You may need to take Colesvir on a long-term basis for the treatment of high cholesterol.
Store Colesvir at room temperature, protected from moisture, heat, and light.
Colesvir administration
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Colesvir is usually taken at bedtime or with an evening meal. If you take Colesvir several times daily, take it with meals. Follow your doctor's instructions.
Your doctor may occasionally change your dose to make sure you get the best results.
Do not crush, chew, or break an extended-release tablet. Swallow it whole. Breaking or opening the pill may cause too much of the drug to be released at one time.
You may need to stop using Colesvir for a short time if you have surgery or a medical emergency.
To be sure this medicine is helping your condition and is not causing harmful effects, your blood will need to be tested often. Your liver function may also need to be tested. Visit your doctor regularly.
Colesvir is only part of a complete program of treatment that also includes diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely.
You may need to take Colesvir on a long-term basis for the treatment of high cholesterol.
Store at room temperature away from moisture, heat, and light.
Colesvir pharmacology
Mechanism of Action
Colesvir is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol.
The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL-C) levels are both associated with coronary heart disease. However, the risk of developing coronary heart disease is continuous and graded over the range of cholesterol levels and many coronary events do occur in patients with total cholesterol (Total-C) and LDL-C levels in the lower end of this range.
Colesvir™ (Colesvir extended-release tablets) has been shown to reduce LDL-C, and Total-C. Across all doses studied, treatment with Colesvir™ (Colesvir extended-release tablets) has been shown to result in variable reductions in triglycerides (TG), and variable increases in HDL-C.
Colesvir immediate-release tablets have been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very low-density lipoprotein (VLDL) and is catabolized predominantly by the high-affinity LDL receptor. The mechanism of the LDL-lowering effect of Colesvir immediate-release may involve both reduction of VLDL-C concentration, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL-C. Apolipoprotein B (Apo B) also falls substantially during treatment with Colesvir immediate-release. Since each LDL particle contains one molecule of Apo B, and since little Apo B is found in other lipoproteins, this strongly suggests that Colesvir immediate-release does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, Colesvir immediate-release can produce increases of variable magnitude in HDL-C, and modestly reduces VLDL-C and plasma TG. The independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. The effects of Colesvir immediate-release on lipoprotein (a) [Lp(a)], fibrinogen, and certain other independent biochemical risk markers for coronary heart disease are unknown.
Colesvir, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance
Pharmacokinetics and Drug Metabolism
Absorption
Colesvir™
The appearance of Colesvir in plasma from an Colesvir (Colesvir extended-release tablets) ™ Extended-Release Tablet is slower and more prolonged compared to the Colesvir immediate-release formulation.
A pharmacokinetic study carried out with Colesvir™ involved measurement of the systemic concentrations of Colesvir (pro-drug), Colesvir acid (active-drug) and total and active inhibitors of HMG-CoA reductase. The pharmacokinetic parameters in 12 hypercholesterolemic subjects at steady state, after 28 days of treatment, comparing Colesvir™ 40 mg to Colesvir immediate-release 40 mg, are summarized in Table I.
Table I: Colesvir™ vs Colesvir Immediate-Release (IR) (Steady-State Pharmacokinetic Parameters at Day 28)
The extended-release properties of Colesvir™ (Colesvir extended-release tablets) are characterized by a prolonged absorptive phase, which results in a longer Tmax and lower Cmax for Colesvir (prodrug) and its major metabolite, Colesvir acid, compared to Colesvir immediate-release.
The bioavailability of Colesvir (pro-drug) as measured by the AUC was greater for Colesvir™ compared to Colesvir immediate-release (as measured by a chemical assay), while the bioavailability of total and active inhibitors of HMG-CoA reductase were equivalent to Colesvir immediate-release (as measured by an enzymatic assay).
With once-a-day dosing, mean values of AUCs of active and total inhibitors at steady state were about 1.8 -1.9 times those following a single dose. Accumulation ratio of Colesvir exposure was 1.5 after multiple daily doses of Colesvir™ (Colesvir extended-release tablets) compared to that of a single dose measured using a chemical assay.
Colesvir™ (Colesvir extended-release tablets) appears to have dose linearity for doses from 10 mg up to 60 mg per day.
When Colesvir™ was given after a meal, plasma concentrations of Colesvir and Colesvir acid were about 0.5 - 0.6 times those found when Colesvir™ (Colesvir extended-release tablets) was administered in the fasting state, indicating that food decreases the bioavailability of Colesvir™ (Colesvir extended-release tablets). There was an association between the bioavailability of Colesvir™ (Colesvir extended-release tablets) and dosing after mealtimes. Bioavailability was lowered under the following conditions, (from higher bioavailability to lower bioavailability) in the following order: under overnight fasting conditions, before bedtime, with dinner, and with a high fat breakfast. In a multicenter, randomized, parallel group study, patients were administered 40 mg of Colesvir™ (Colesvir extended-release tablets) at three different times; before breakfast, after dinner and at bedtime. Although there was no statistical difference in the extent of lipid change between the three groups, there was a numerically greater reduction in LDL-C and TG and an increase in HDL-C when Colesvir™ (Colesvir extended-release tablets) was administered at bedtime. Results of this study are displayed in Table II.
Table II: Colesvir™ (Colesvir extended-release tablets) 40 mg (Least Squares Mean Percent Changes from Baseline to Endpoint at 4 weeks of treatment*)
The distribution of LDL-C responses is represented graphically by the boxplots in Figure 2. The bottom line of the box represents the 25th percentile and the top line, the 75th percentile. The horizontal line in the box represents the median and the gray area is the 95% confidence interval for the median. The range of responses is depicted by the tails and outliers.
Colesvir™ (Colesvir extended-release tablets) Long-Term Study
A total of 365 patients were enrolled in an extension study in which all patients were administered Colesvir™ (Colesvir extended-release tablets) 40 mg or 60 mg once daily for up to 6 months of treatment. The lipid-altering effects of Colesvir™ (Colesvir extended-release tablets) were comparable to what was observed in the dose-response study, and were maintained for up to 6 months of treatment.
Special Populations
In clinical studies with Colesvir™ (Colesvir extended-release tablets), there were no statistically significant differences in LDL-C reduction in an older population ( ≥ 65 years old), compared to a younger population ( < 65 years old). There were also no statistically significant differences in LDL-C reduction between male and female patients.
Colesvir Immediate-Release
Colesvir immediate-release has been shown to be effective in reducing Total-C and LDL-C in heterozygous familial and non-familial forms of primary hypercholesterolemia and in mixed hyperlipidemia. A marked response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks. The response was maintained during continuation of therapy. Single daily doses given in the evening were more effective than the same dose given in the morning, perhaps because cholesterol is synthesized mainly at night.
Colesvir immediate-release was studied in controlled trials in hypercholesterolemic patients with well-controlled non-insulin dependent diabetes mellitus with normal renal function. The effect of Colesvir immediate-release on lipids and lipoproteins and the safety profile of Colesvir immediate-release were similar to that demonstrated in studies in nondiabetics. Colesvir immediate-release had no clinically important effect on glycemic control or on the dose requirement of oral hypoglycemic agents.
Expanded Clinical Evaluation of Colesvir (EXCEL) Study
Colesvir immediate-release was compared to placebo in 8,245 patients with hypercholesterolemia [Total-C 240-300 mg/dL (6.2 mmol/L-7.6 mmol/L), LDL-C > 160 mg/dL (4.1 mmol/L)] in the randomized, double-blind, parallel, 48-week EXCEL study. All changes in the lipid measurements observed in Colesvir immediate-release-treated patients were dose-related and significantly different from placebo (p ≤ 0.001). These results were sustained throughout the study.
TABLE IV: Colesvir Immediate-Release (IR) vs. Placebo (Percent Change from Baseline - Average Values Between Weeks 12 and 48)
Atherosclerosis
In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect of therapy with Colesvir on coronary atherosclerosis was assessed by coronary angiography in hyperlipidemic patients. In this randomized, double-blind, controlled clinical trial, patients were treated with conventional measures (usually diet and 325 mg of aspirin every other day) and either Colesvir 20 mg - 80 mg daily or placebo. Angiograms were evaluated at baseline and at two years by computerized quantitative coronary angiography (QCA). Colesvir significantly slowed the progression of lesions as measured by the mean change per-patient in minimum lumen diameter (the primary endpoint) and percent diameter stenosis, and decreased the proportions of patients categorized with disease progression (33% vs. 50%) and with new lesions (16% vs. 32%).
In a similarly designed trial, the Monitored Atherosclerosis Regression Study (MARS), patients were treated with diet and either Colesvir 80 mg daily or placebo. No statistically significant difference between Colesvir and placebo was seen for the primary endpoint (mean change per patient in percent diameter stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by angiographers who formed a consensus opinion of overall angiographic change (Global Change Score) was also a secondary endpoint. By this endpoint, significant slowing of disease was seen, with regression in 23% of patients treated with Colesvir compared to 11% of placebo patients.
The effect of Colesvir on the progression of atherosclerosis in the coronary arteries has been corroborated by similar findings in another vasculature. In the Asymptomatic Carotid Artery Progression Study (ACAPS), the effect of therapy with Colesvir on carotid atherosclerosis was assessed by B-mode ultrasonography in hyperlipidemic patients with early carotid lesions and without known coronary heart disease at baseline. In this double- blind, controlled clinical trial, 919 patients were randomized in a 2 x 2 factorial design to placebo, Colesvir 10-40 mg daily and/or warfarin. Ultrasonograms of the carotid walls were used to determine the change per patient from baseline to three years in mean maximum intimal-medial thickness (IMT) of 12 measured segments. There was a significant regression of carotid lesions in patients receiving Colesvir alone compared to those receiving placebo alone (p=0.001). The predictive value of changes in IMT for stroke has not yet been established. In the Colesvir group there was a significant reduction in the number of patients with major cardiovascular events relative to the placebo group (5 vs. 14) and a significant reduction in all-cause mortality (1 vs. 8).
Eye
There was a high prevalence of baseline lenticular opacities in the patient population included in the early clinical trials with Colesvir immediate-release. During these trials the appearance of new opacities was noted in both the Colesvir immediate-release and placebo groups. There was no clinically significant change in visual acuity in the patients who had new opacities reported nor was any patient, including those with opacities noted at baseline, discontinued from therapy because of a decrease in visual acuity.
A three-year, double-blind, placebo-controlled study in hypercholesterolemic patients to assess the effect of Colesvir immediate-release on the human lens demonstrated that there were no clinically or statistically significant differences between the Colesvir immediate-release and placebo groups in the incidence, type or progression of lenticular opacities. There are no controlled clinical data assessing the lens available for treatment beyond three years.
REFERENCES
1. Kantola, T, et al. Clin Pharmacol Ther 1998; 63(4):397-402.
References
- DailyMed. "LOVASTATIN: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Lovastatin: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Lovastatin: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
The results of a survey conducted on ndrugs.com for Colesvir are given in detail below. The results of the survey conducted are based on the impressions and views of the website users and consumers taking Colesvir. We implore you to kindly base your medical condition or therapeutic choices on the result or test conducted by a physician or licensed medical practitioners.User reports
Consumer reported administration
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Information checked by Dr. Sachin Kumar, MD Pharmacology
