Simvastatin

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Simvastatin, also known as Zocor

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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. [4][5]

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)[6] 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. [7]

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. Cmax values of Simvastatin (40mg doses) increased by nearly 300%, tmax increased 100%,, the half life decreased by 50%, and AUC increased by nearly 300%. These results are even more pronounced for active Simvastatin metabolites. [8]
  • 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. [9]

References

  1. ↑ http://money.cnn.com/2006/06/23/news/companies/zoloft_zocor/index.htm
  2. ↑ Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001 May 11;292(5519):1160-4. PMID:11349148 doi:10.1126/science.1059344
  3. ↑ Corsini A, Maggi FM, Catapano AL. Pharmacology of competitive inhibitors of HMG-CoA reductase. Pharmacol Res. 1995 Jan;31(1):9-27. PMID:7784310
  4. ↑ Illingworth DR, Crouse JR 3rd, Hunninghake DB, Davidson MH, Escobar ID, Stalenhoef AF, Paragh G, Ma PT, Liu M, Melino MR, O'Grady L, Mercuri M, Mitchel YB. A comparison of simvastatin and atorvastatin up to maximal recommended doses in a large multicenter randomized clinical trial. Curr Med Res Opin. 2001;17(1):43-50. PMID:11464446
  5. ↑ Weng TC, Yang YH, Lin SJ, Tai SH. A systematic review and meta-analysis on the therapeutic equivalence of statins. J Clin Pharm Ther. 2010 Apr;35(2):139-51. PMID:20456733 doi:10.1111/j.1365-2710.2009.01085.x
  6. ↑ Weng TC, Yang YH, Lin SJ, Tai SH. A systematic review and meta-analysis on the therapeutic equivalence of statins. J Clin Pharm Ther. 2010 Apr;35(2):139-51. PMID:20456733 doi:10.1111/j.1365-2710.2009.01085.x
  7. ↑ http://www.reuters.com/article/idUSTRE62I3YW20100319
  8. ↑ Lilja JJ, Neuvonen M, Neuvonen PJ. Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. Br J Clin Pharmacol. 2004 Jul;58(1):56-60. PMID:15206993 doi:10.1111/j.1365-2125.2004.02095.x
  9. ↑ http://timesofindia.indiatimes.com/business/india-business/Mercks-Zocor-price-cut-a-mixed-bag-for-drug-cos/articleshow/1690722.cms


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