Simvastatin

Absorption

Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours post-dose. While the recommended therapeutic dose range is 10 to 40 mg/day, there was no substantial deviation from linearity of AUC with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before a test meal.
In a pharmacokinetic study of 17 healthy Chinese volunteers, the major PK parameters were as follows: Tmax 1.44 hours, Cmax 9.83 ug/L, t1/2 4.85 hours, and AUC 40.32ug·h/L.
Simvastatin undergoes extensive first-pass extraction in the liver, the target organ for the inhibition of HMG-CoA reductase and the primary site of action. This tissue selectivity (and consequent low systemic exposure) of orally administered simvastatin has been shown to be far greater than that observed when the drug is administered as the enzymatically active form, i.e. as the open hydroxyacid.
In animal studies, after oral dosing, simvastatin achieved substantially higher concentrations in the liver than in non-target tissues. However, because simvastatin undergoes extensive first-pass metabolism, the bioavailability of the drug in the systemic system is low. In a single-dose study in nine healthy subjects, it was estimated that less than 5% of an oral dose of simvastatin reached the general circulation in the form of active inhibitors.
Genetic differences in the OATP1B1 (Organic-Anion-Transporting Polypeptide 1B1) hepatic transporter encoded by the SCLCO1B1 gene (Solute Carrier Organic Anion Transporter family member 1B1) have been shown to impact simvastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c.521T>C single nucleotide polymorphism (SNP) showed that simvastatin plasma concentrations were increased on average 3.2-fold for individuals homozygous for 521CC compared to homozygous 521TT individuals. The 521CC genotype is also associated with a marked increase in the risk of developing myopathy, likely secondary to increased systemic exposure. Other statin drugs impacted by this polymorphism include rosuvastatin, pitavastatin, atorvastatin, lovastatin, and pravastatin.
For patients known to have the above-mentioned c.521CC OATP1B1 genotype, a maximum daily dose of 20mg of simvastatin is recommended to avoid adverse effects from the increased exposure to the drug, such as muscle pain and risk of rhabdomyolysis.
Evidence has also been obtained with other statins such as rosuvastatin that concurrent use of statins and inhibitors of Breast Cancer Resistance Protein (BCRP) such as elbasvir and grazoprevir increased the plasma concentration of these statins. Further evidence is needed, however a dose adjustment of simvastatin may be necessary. Other statin drugs impacted by this polymorphism include fluvastatin and atorvastatin.

Description

Simvastatin is an once-daily hypolipemic, an analog of lovastatin indicated for the treatment of atherosclerosis. In patients with Type IN or IIB hypercholesterolemia, simvastatin reportedly produces significant reductions in total serum cholesterol, LDL, mglycerides and apolipoprotein-B, while HDL and apolipoprotein-A levels are increased.

Description

Simvastatin (Zocor) is a cholesterol-lowering drug that was developed in parallel with lovastatin. The only difference between the two is that simvastatin has an extra methyl group in the butanoate ester moiety. Simvastatin was introduced in the late 1980s and is now available as a generic drug under several names.

Chemical properties

White Powder

Originator

Merck (USA)

The Uses of Simvastatin

Simvastatin is a synthetic derivate of a fermentation product of Aspergillus terreus. A competitive inhibitor of HMG-CoA reductase. A synthetic analog of Lovastatin. Antilipemic. Simvastatin, the drug, is sold under the trade name Zocor.

The Uses of Simvastatin

antiinflammatory

The Uses of Simvastatin

Simvastatin is a synthetic derivative of a fermentation product of Aspergillus terreus. A competitive inhibitor of HMG-CoA reductase. A synthetic analog of Lovastatin. Antilipemic. Simvastatin, the dr ug, is sold under the trade name Zocor.

The Uses of Simvastatin

Simvastatin is semi-synthetic, slightly more hydrophobic, analogue of lovastatin. Like lovastatin, simvastatin is a specific inhibitor of HMG-CoA reductase and is used therapeutically to reduce LDL cholesterol. More recently, the statins have become important biochemical probes in cell biology. Their involvement in many events can be correlated to their primary mode of action, however, the mechanism of action of many other effects is less apparent.

The Uses of Simvastatin

anti-hyperlipoproteinemic, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor

The Uses of Simvastatin

A HMGCR inhibitor and anti-proliferative agent.

Background

Simvastatin, also known as the brand name product Zocor, is a lipid-lowering drug derived synthetically from a fermentation product of Aspergillus terreus. It belongs to the statin class of medications, which are used to lower the risk of cardiovascular disease and manage abnormal lipid levels by inhibiting the endogenous production of cholesterol in the liver. More specifically, statin medications competitively inhibit the enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) Reductase, which catalyzes the conversion of HMG-CoA to mevalonic acid and is the third step in a sequence of metabolic reactions involved in the production of several compounds involved in lipid metabolism and transport including cholesterol, low-density lipoprotein (LDL) (sometimes referred to as "bad cholesterol"), and very low-density lipoprotein (VLDL). Prescribing of statin medications is considered standard practice following any cardiovascular events and for people with a moderate to high risk of development of CVD, such as those with Type 2 Diabetes. The clear evidence of the benefit of statin use coupled with very minimal side effects or long term effects has resulted in this class becoming one of the most widely prescribed medications in North America.
Simvastatin and other drugs from the statin class of medications including atorvastatin, pravastatin, rosuvastatin, fluvastatin, and lovastatin are considered first-line options for the treatment of dyslipidemia. Increasing use of the statin class of drugs is largely due to the fact that cardiovascular disease (CVD), which includes heart attack, atherosclerosis, angina, peripheral artery disease, and stroke, has become a leading cause of death in high-income countries and a major cause of morbidity around the world. Elevated cholesterol levels, and in particular, elevated low-density lipoprotein (LDL) levels, are an important risk factor for the development of CVD. Use of statins to target and reduce LDL levels has been shown in a number of landmark studies to significantly reduce the risk of development of CVD and all-cause mortality. Statins are considered a cost-effective treatment option for CVD due to their evidence of reducing all-cause mortality including fatal and non-fatal CVD as well as the need for surgical revascularization or angioplasty following a heart attack. Evidence has shown that even for low-risk individuals (with <10% risk of a major vascular event occurring within 5 years) statins cause a 20%-22% relative reduction in major cardiovascular events (heart attack, stroke, coronary revascularization, and coronary death) for every 1 mmol/L reduction in LDL without any significant side effects or risks.
While all statin medications are considered equally effective from a clinical standpoint, rosuvastatin is considered the most potent; doses of 10 to 40mg rosuvastatin per day were found in clinical studies to result in a 45.8% to 54.6% decrease in LDL cholesterol levels, while simvastatin has been found to have an average decrease in LDL-C of ~35%. Potency is thought to correlate to tissue permeability as the more lipophilic statins such as simvastatin are thought to enter endothelial cells by passive diffusion, as opposed to hydrophilic statins such as pravastatin and rosuvastatin which are taken up into hepatocytes through OATP1B1 (organic anion transporter protein 1B1)-mediated transport. Despite these differences in potency, several trials have demonstrated only minimal differences in terms of clinical outcomes between statins.

Indications

Simvastatin is indicated for the treatment of hyperlipidemia to reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL?C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C).
This includes the treatment of primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial), mixed dyslipidemia (Fredrickson type IIb), hypertriglyceridemia (Fredrickson type IV hyperlipidemia), primary dysbetalipoproteinemia (Fredrickson type III hyperlipidemia), homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments, as well as adolescent patients with Heterozygous Familial Hypercholesterolemia (HeFH).
Simvastatin is also indicated to reduce the risk of cardiovascular morbidity and mortality including myocardial infarction, stroke, and the need for revascularization procedures. It is primarily used in patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease.
Prescribing of statin medications is considered standard practice following any cardiovascular events and for people with a moderate to high risk of development of CVD. Statin-indicated conditions include diabetes mellitus, clinical atherosclerosis (including myocardial infarction, acute coronary syndromes, stable angina, documented coronary artery disease, stroke, trans ischemic attack (TIA), documented carotid disease, peripheral artery disease, and claudication), abdominal aortic aneurysm, chronic kidney disease, and severely elevated LDL-C levels.

What are the applications of Application

Simvastatin is a HMGCR inhibitor and anti-proliferative agent

Definition

ChEBI: A carbobicyclic compound that is lovastatin in which the 2-methylbutyrate ester moiety has been replaced by a 2,2-dimethylbutyrate ester group. It is used as a cholesterol-lowering and anti-cardiovascular disease drug.

Manufacturing Process

A suspension of Lovastatin (350 g, 0.865 mmol), phenylboronic acid (110.8 g, 0.909 mmol) and toluene (1.75 L) was heated under a nitrogen atmosphere at 100-105°C for 55 min. The water was separated from the reaction mixture. The solution was cooled and 1.39 L of toluene was removed by vacuum distillation at 40-50°C. The concentrated solution was treated with hexanes (3.15 L) at 40-50°C. The resulting suspension was cooled to 0-5C for 2 hours and the product was filtered and washed with hexanes (350 mL). The product was dried at 35-40°C under vacuum to provide 427.9 g (37%) of lovastatin phenylboronate at >99% purity by HPLC.
A 2 L 3-necked flask was charged with pyrrolidine (56 mL, 0.67 mol) and dry THF (453 g) under a nitrogen atmosphere. n-Butyl lithium (419 mL, 1.6 M hexane solution, 0.67 mol) was added dropwise at -20°C over a period of 1 hour. The solution was maintained at this temperature for 30 min and then cooled to -55°C. A solution of lovastatin phenylboronate (101.7 g, 0.20 mol) in 274.7 g of THF was cooled to -50°C and then added to the cold lithium pyrrolidide solution at a rate such that the internal temperature was between -50°-55°C during the addition. The mixture was held at this temperature for 4 hours and then methyl iodide (116.4 g, 0.82 mol) was added at a temperature below -55°C. The reaction was stirred for 13 hours at -20°C and then quenched with 500 mL of 2 M HCl at a temperature below 0°C. After warming to 20°C, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 5% NaHSO3 solution and deionized water. The solution was filtered through a Celite pad and concentrated to yield 102.8 g (98.4%) of crude Simvastatin phenylboronate at >95% purity by HPLC. A portion of the above material (50.0 g) was charged into a nitrogen purged flask with acetonitrile (100 mL). The suspension was heated at 110°C for 3 hours and then cooled to - 10°C for 1 hour. The product was filtered and washed with 25 mL of acetonitrile and dried under vacuum to provide 43.7 g of Simvastatin phenylboronate at >99% purity by HPLC.
A suspension of simvastatin phenylboronate (30.0 g) and 1,3-propanediol (450 mL) was heated at 105-107°C at 0.2 mm Hg. After 1 hour, 182 mL of distillate was collected and the reaction was cooled to 20-25°C. Deionized water (270 mL) was added and toluene (3 times 75 mL) was used to extract the mixture. The combined toluene layers were washed with water (60 mL). The organic solution was heated at reflux for 1 hour and water was azeotropically removed. The solution was concentrated to a final volume of 24 mL under vacuum at 48-50°C. To the concentrated solution was added hexanes (215 mL) over 10 min. The resulting slurry was cooled to 0-5°C and filtered. The crude Simvastatin was washed at 0-5°C with hexanes and dried under vacuum to yield 21.0 g (88%) of Simvastatin.

brand name

Zocor (Merck);Zocord.

Therapeutic Function

Antihyperlipidemic

General Description

Simvastatin, 2,2-dimethyl butanoic acid,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2-pyran-2-yl)ethyl]-1-naphthalenyl ester(Zocor), is an analog of lovastatin. These two drugs havemany similar properties. Both drugs, in the prodrug form,reach the liver unchanged after oral administration, wherethey undergo extensive metabolism to several open-ring hydroxyacids, including the active -hydroxy acids. They arealso highly bound to plasma proteins. These actions makethe bioavailability of simvastatin rather poor but better thanthat of lovastatin, which has been estimated to be 5%.

Biological Activity

HMG-CoA reductase inhibitor; decreases levels of low density lipoprotein. Has multiple biological effects including bone formation stimulation, inhibition of smooth muscle cell proliferation and migration, and anticancer and anti-inflammatory activity.

Biochem/physiol Actions

Simvastatin is a specific inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early step in cholesterol biosynthesis. It is used in the treatment of hypercholesterolemia, as it reduces levels of low-density lipoproteins and triglycerides, and raises high-density lipoprotein levels. Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, and can be activated prior to use with NaOH in EtOH treatment. It is a synthetic analog of lovastatin (Cat. No. M2147).

Pharmacokinetics

Simvastatin is an oral antilipemic agent which inhibits HMG-CoA reductase. It is used to lower total cholesterol, low density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apoB), non-high density lipoprotein-cholesterol (non-HDL-C), and trigleride (TG) plasma concentrations while increasing HDL-C concentrations. High LDL-C, low HDL-C and high TG concentrations in the plasma are associated with increased risk of atherosclerosis and cardiovascular disease. The total cholesterol to HDL-C ratio is a strong predictor of coronary artery disease and high ratios are associated with higher risk of disease. Increased levels of HDL-C are associated with lower cardiovascular risk. By decreasing LDL-C and TG and increasing HDL-C, rosuvastatin reduces the risk of cardiovascular morbidity and mortality.
Elevated cholesterol levels, and in particular, elevated low-density lipoprotein (LDL) levels, are an important risk factor for the development of CVD. Use of statins to target and reduce LDL levels has been shown in a number of landmark studies to significantly reduce the risk of development of CVD and all-cause mortality. Statins are considered a cost-effective treatment option for CVD due to their evidence of reducing all-cause mortality including fatal and non-fatal CVD as well as the need for surgical revascularization or angioplasty following a heart attack. Evidence has shown that even for low-risk individuals (with <10% risk of a major vascular event occurring within 5 years) statins cause a 20%-22% relative reduction in major cardiovascular events (heart attack, stroke, coronary revascularization, and coronary death) for every 1 mmol/L reduction in LDL without any significant side effects or risks.
Skeletal Muscle Effects
Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. Chinese patients may also be at increased risk for myopathy. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued.
In a clinical trial database of 41,413 patients, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively, while the risk of myopathy with simvastatin 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. It's therefore recommended that the 80mg dose of simvastatin should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. As well, patients already stabilized on simvastatin 80mg should be monitored closely for evidence of muscle toxicity; if they need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug interaction.
The risk of myopathy during treatment with simvastatin may be increased with concurrent administration of interacting drugs such as fenofibrate, niacin, gemfibrozil, cyclosporine, and strong inhibitors of the CYP3A4 enzyme. Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with colchicine, and caution should therefore be exercised when prescribing these two medications together.
Liver Enzyme Abnormalities
Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms.
In the Scandinavian Simvastatin Survival Study (4S), the number of patients with more than one transaminase elevation to >3 times the ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]). The frequency of single elevations of ALT to 3 times the ULN was significantly higher in the simvastatin group in the first year of the study (20 vs. 8, p=0.023), but not thereafter. In the HPS (Heart Protection Study), in which 20,536 patients were randomized to receive simvastatin 40 mg/day or placebo, the incidences of elevated transaminases (>3X ULN confirmed by repeat test) were 0.21% (n=21) for patients treated with simvastatin and 0.09% (n=9) for patients treated with placebo.
Endocrine Effects
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.
Although cholesterol is the precursor of all steroid hormones, studies with simvastatin have suggested that this agent has no clinical effect on steroidogenesis. Simvastatin caused no increase in biliary lithogenicity and, therefore, would not be expected to increase the incidence of gallstones.

Clinical Use

HMG CoA reductase inhibitor:
Primary hypercholesterolaemia

Drug interactions

Potentially hazardous interactions with other drugs
Anti-arrhythmics: increased risk of myopathy with amiodarone - do not exceed 20 mg of simvastatin1 ; increased risk of myopathy with dronedarone.
Antibacterials: increased risk of myopathy with clarithromycin, daptomycin, erythromycin and fusidic acid - avoid; possibly increased myopathy with azithromycin; concentration possibly reduced by rifampicin.
Anticoagulants: effects of coumarins enhanced.
Antiepileptics: concentration reduced by carbamazepine and eslicarbazepine.
Antifungals: increased risk of myopathy with fluconazole, itraconazole, posaconazole, ketoconazole, voriconazole and possibly miconazole - avoid; possibly increased risk of myopathy with imidazoles.
Antivirals: increased risk of myopathy with atazanavir, indinavir, lopinavir, ritonavir or saquinavir and possibly fosamprenavir, lopinavir or tipranavir - avoid; concentration reduced by efavirenz; avoid with boceprevir, dasabuvir, ombitasvir, paritaprevir and telaprevir; possible increased risk of myopathy with ledipasvir - reduce simvastatin dose; concentration increased by simeprevir - consider reducing simvastatin dose.
Calcium-channel blockers: increased risk of myopathy with verapamil, diltiazem and amlodipine - do not exceed 20 mg of simvastatin.1
Ciclosporin: increased risk of myopathy - avoid.1
Cobicistat: avoid with simvastatin.
Colchicine: possible increased risk of myopathy.
Grapefruit: increased risk of myopathy - avoid.
Hormone antagonists: possibly increased risk of myopathy with danazol - avoid.1
Lipid-lowering agents: increased risk of myopathy with fibrates - do not exceed 10 mg of simvastatin except with fenofibrate1 ; gemfibrozil - avoid; concentration increased by lomitapide - do not exceed 40 mg of simvastatin; increased risk of myopathy with nicotinic acid.
Ranolazine: concentration increased by ranolazine, maximum dose of simvastatin is 20 mg.
Ticagrelor: concentration of simvastatin increased; maximum dose of simvastatin is 40 mg

Metabolism

Simvastatin is administered as the inactive lactone derivative that is then metabolically activated to its β-hydroxyacid form by a combination of spontaneous chemical conversion and enzyme-mediated hydrolysis by nonspecific carboxyesterases in the intestinal wall, liver, and plasma. Oxidative metabolism in the liver is primarily mediated by CYP3A4 and CYP3A5, with the remaining metabolism occurring through CYP2C8 and CYP2C9.
The major active metabolites of simvastatin are β-hydroxyacid metabolite and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives.
Polymorphisms in the CYP3A5 gene have been shown to affect the disposition of simvastatin and may provide a plausible explanation for interindividual variability of simvastatin disposition and pharmacokinetics.

Metabolism

Simvastatin is absorbed from the gastrointestinal tract and must be hydrolysed to its active β-hydroxyacid form. Other active metabolites have been detected and several inactive metabolites are also formed. Simvastatin is a substrate for the cytochrome P450 isoenzyme CYP3A4 and undergoes extensive first-pass metabolism in the liver, its primary site of action. Less than 5% of an oral dose has been reported to reach the circulation as active metabolites.
Simvastatin is mainly excreted in the faeces via the bile as metabolites. About 10-15% is recovered in the urine, mainly in inactive forms.

storage

Desiccate at -20°C

References

References/Citations 1) Merck 14:8539 2) Hancock et al. (1989), All ras proteins are polyisoprenylated but only some are palmitoylated; Cell, 57 1167 3) Ose et al. (2000), Lipid-altering efficacy and safety of simvastatin 80 mg/day: long-term experience in a large group of patients with hypercholesterolemia. World Wide Expanded Dose Simvastatin Study Group Clin. Cardiol. 23 39 4) Matsuzaka et al. (2016) Characterization and functional analysis of extracellular vesicles and muscle-abundant miRNA in C2C12 myocytes and Mdx mice; PLoS One 11(12) e0167811 [Focus Biomolecules Citation]