Simvastatin

spinqualitylabelsall models Simvastatin, also known as Zocor Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Better Known as: Zocor

• Marketed By: Merck & Co. Inc.
  
• Major Indication: Hyperlipidemia & High Cholesterol (Hypercholesterolemia)
  
• Drug Class: HMGR Inhibitor or Statin
• Date of FDA Approval (Patent Expiration): 1997 (2006)
  
• 2005 Sales: $4.4 Billion
• Importance: Zocor is one of the best selling drugs of all time and was the second best selling drug in 2005 before going off patent. Since statins are so ubiquitous, doctors have even suggested handing them out with fast food. See: the article
  
• See Pharmaceutical Drugs for more information about other drugs and disorders

Mechanism of Action

Simvastatin is rapidly hydrolyzed in vivo to generate mevinolinic acid, a powerful inhibitor of HMG-CoA Reductase (HMGR). HMGR is a responsible for the committed step in cholesterol synthesis. Simvastatin, like other statins, via a number of polar interactions with the "cis loop" of HMGR, particularly residues Ser 684, Asp 690, Lys 691, Lys 692, and hydrogen bond interactions between Glu 559 and Asp 767 with the O5-hydroxyl of the statins. Van der Waals interactions between Leu 562, Val 683, Leu 853, Ala 856, and Leu 857 of HMGR and hydrophobic ring structures of Simvastatin help form the pocket the drug is positioned in. These interactions help Simvastatin outcompete HMG-CoA, the substrate of HMGR, in binding to HMGR.

Pharmacokinetics

Statin Pharmacokinetics at 10mg Dosage Parameter Atorvastatin (Lipitor) Fluvastatin (Lescol) Lovastatin (Mevacor) Simvastatin (Zocor) Rosuvastatin (Crestor) Cerivastatin (Baycol) Tmax (hr) 2.5 1 3 1.5 4 1.5 Cmax (ng/ml) 27-66 448 10-20 7.3 4.34 3.43 Bioavailability (%) 12 19-29 5 5 20 60 Protein Binding (%) 80-90 99 95 95 88 99 T1/2 (hr) 15-30 2 3 2.7 19 2.2 AUC (ng/ml/hr) 104 ~150 33 125 48 14.5 IC50 (nM) 154 198 800 66 320 50-90 Equivalent LDL Reduction Dosage (mg) 10 -- 80 20 5 -- Metabolism Hepatic (CYP3A4) Hepatic (CYP2C9) Hepatic (CYP3A4) Hepatic (CYP3A4) None Hepatic (CYP2C8) For References, See References

Effectiveness and Side Effects

Effectiveness

At the 20mg dose, Simvastatin reduces LDL concentration by 30-40%, in line with 5mg of Rosuvastatin (Crestor) and 10mg of Atorvastatin (Lipitor). Of particular note, at the 20mg dosage, Simvastatin had the most variable results, with patients experiencing drops in LDL ranging from 20%, well below the minimum of Crestor and Lipitor, to as high as 55%, as high as the maximum, 80mg dosage of Lipitor. At 80mg, Atorvastatin appears to be more effective at preventing coronary heart disease compared to 20mg Simvastatin, but considering the variation in dosage level, it is difficult to directly compare these results.

Side Effects

The Statins are one of the safest drug classes to reach block buster status. Typical adverse events include muscle weakness, headache dizziness and slightly increased creatinine kinase (CK) levels (an indication of kidney and smooth muscle damage), although these are common to all the statins (with the exception of elevated CK levels which only occurs in Atorvastatin, Rosuvastatin, and Simvastatin) In March, 2010, the FDA issued a warning about an increased rate of Rhabdomyolysis, a dangerous breakdown of muscle fiber, releasing myoglobin into the bloodstream, potentially resulting in severe kidney damage. Although these concerns are not enough to have patients cease use of Zocor, it is important for the public to be aware of the issue.

Interesting Facts

• As with other statins which are metabolized by the CYP3A4 liver enzyme, the pharmacokinetics of Simvastatin are altered significantly by consumption of grapefruit juice. C_max values of Simvastatin (40mg doses) increased by nearly 300%, t_max increased 100%,, the half life decreased by 50%, and AUC increased by nearly 300%. These results are even more pronounced for active Simvastatin metabolites.
• Simvastatin is simply the methyalted form of Lovastatin an earlier Statin developed by Merck.

The Jist

Along with the other statins, Simvastatin works well and is quite safe. Depending upon the patient, Simvastatin can be the most effective statin at reducing LDL, but can also have dramatically reduced efficacy. Since Simvastatin is the most powerful HMGR inhibitor with an IC₅₀ of 66nM, this allows for decreased long-term exposure to the drug (lower AUC) and negates the short half life of Simvastatin compared to Atorvastatin and Rosuvastatin. While on patent it was one of the best selling drugs in the world. To maintain its market share after losing patent protection, Merck dramatically reduced the price of Zocor for insurance companies well below the price of existing statin generics, making the drug particularly attractive to US Health Insurers looking to reduce costs.