Simvastatin
|
Better Known as: Crestor
- Marketed By: AstraZeneca Plc.
- Major Indication: Hyperlipidemia & High Cholesterol (Hypercholesterolemia)
- Drug Class: HMGR Inhibitor or Statin
- Date of FDA Approval (Patent Expiration): 2003 (2016)
- 2009 Sales: $4.5 Billion [1]
- Why You Should Care: Sales of Crestor are the fastest growing among the statins. Statins are so ubiquitous, doctors have even suggested handing them out with fast food. See: the article
- The following is a list of Pharmacokinetic Parameters. See: Pharmaceutical Drugs for more information
Mechanism of Action
Rosuvastatin is an inhibitor of HMG-CoA Reductase (HMGR), a responsible for the committed step in cholesterol synthesis. Rosuvastatin, like most of the 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 Rosuvastatin contribute to binding as well.[2] These interactions help Rosuvastatin outcompete HMG-CoA, the substrate of HMGR, in binding to HMGR.[3]
Pharmacokinetics
| Statin PK Comparison at 10mg doses[4][5][6][7] | |||||
|---|---|---|---|---|---|
| Parameter | Atorvastatin (Lipitor) | Fluvastatin (Lescol) | Lovastatin (Mevacor) | Simvastatin (Zocor) | Rosuvastatin (Crestor) |
| Tmax (hr) | 2.5 | 1 | 3 | 1.5 | 4 |
| Cmax (ng/ml) | 27-66 | 448 | 10-20 | 7.3 | 4.34 |
| Bioavailability (%) | 12 | 19-29 | 5 | 5 | 20 |
| Protein Binding (%) | 80-90 | 99 | 95 | 95 | 88 |
| T1/2 (hr) | 15-30 | 2 | 3 | 2.7 | 19 |
| AUC (ng/ml/hr) | 104 | 33 | 125 | 48 | |
| IC50 (nM) | 154 | 198 | 800-4200 | 66 | 320 |
| Equivalent LDL Reduction Dosage (mg) | 10 | 80 | 20 | 5 | |
| Metabolism | Hepatic (CYP3A4) |
Hepatic (CYP2C9) |
Hepatic (CYP3A4) |
Hepatic (CYP3A4) |
Not Metabolized |
Effectiveness and Side Effects
Effectiveness
Rosuvastatin has the greatest efficacy compared to other statins at the same dosage. At 5mg, patients experienced a 40% or greater reduction in LDL as compared to similar results for Atorvastatin at 20mg doses. [8]
Side Effects
Although all of the statins are generally considered safe, rosuvastatin had a higher reported adverse event rate than other statin clinical trials. 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)[9]
Interesting Facts
- Rosuvastatin has made recent headlines as being nearly equivalent in efficacy to Lipitor, but also cuts the rate of heart attacks and strokes significantly. [10]
- Unlike other statins, consuming grapefruit juice does not affect the PKs of rosuvastatin. [11] [12]
- Studies have reveal that that Asians appear to process rosuvastatin differently than members of other races with Cmax and AUC reaching levels which were over 2 fold greater. The FDA has subsequently announced that asians should take half the standard dose to achieve the same cholesterol lowering benefit. [13]
The Jist
The statins are generally viewed as very safe and have been proven effective over the past 15 years. Rosuvastatin is the newest major blockbuster statin and was designed to be taken at lower levels than other statins. Recent studies have indicated rosuvastatin can reduce the likely hood of myocardial infarction and stroke, although this has been refuted by some studies. Truth be told, with major statins like Lipitor coming off patent in the next year or two, pharmaceutical companies are looking for new diseases that can be treated by still-patented statins like Rosuvastatin (Patent expires in 2016). With $4 billion in sales per year and Lipitor going off patent in 2011, resulting in a dramatic price drop in statins as generics flood the market, proving that Rosuvastatin reduces heart attacks, etc. would be worth many billions of dollars. It remains to be seen whether the potential reduction in heart ailments while taking Rosuvastatin, if it exists, can be proven with statistical significance.
References
- ↑ http://www.reuters.com/article/idUSN2223558720100222
- ↑ 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
- ↑ Corsini A, Maggi FM, Catapano AL. Pharmacology of competitive inhibitors of HMG-CoA reductase. Pharmacol Res. 1995 Jan;31(1):9-27. PMID:7784310
- ↑ Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation. 2004 Jun 15;109(23 Suppl 1):III50-7. PMID:15198967 doi:10.1161/01.CIR.0000131519.15067.1f
- ↑ Lins RL, Matthys KE, Verpooten GA, Peeters PC, Dratwa M, Stolear JC, Lameire NH. Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients. Nephrol Dial Transplant. 2003 May;18(5):967-76. PMID:12686673
- ↑ Kiser JJ, Gerber JG, Predhomme JA, Wolfe P, Flynn DM, Hoody DW. Drug/Drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):570-8. PMID:18176327 doi:10.1097/QAI.0b013e318160a542
- ↑ Li P, Callery PS, Gan LS, Balani SK. Esterase inhibition by grapefruit juice flavonoids leading to a new drug interaction. Drug Metab Dispos. 2007 Jul;35(7):1203-8. Epub 2007 Apr 23. PMID:17452418 doi:10.1124/dmd.106.013904
- ↑ 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
- ↑ 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
- ↑ Everett BM, Glynn RJ, MacFadyen JG, Ridker PM. Rosuvastatin in the prevention of stroke among men and women with elevated levels of C-reactive protein: justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). Circulation. 2010 Jan 5;121(1):143-50. Epub 2009 Dec 21. PMID:20026779 doi:10.1161/CIRCULATIONAHA.109.874834
- ↑ Kantola T, Kivisto KT, Neuvonen PJ. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther. 1998 Apr;63(4):397-402. PMID:9585793 doi:10.1016/S0009-9236(98)90034-0
- ↑ Ohta T, Nagahashi M, Hosoi S, Tsukamoto S. Dihydroxybergamottin caproate as a potent and stable CYP3A4 inhibitor. Bioorg Med Chem. 2002 Apr;10(4):969-73. PMID:11836106
- ↑ Lee E, Ryan S, Birmingham B, Zalikowski J, March R, Ambrose H, Moore R, Lee C, Chen Y, Schneck D. Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther. 2005 Oct;78(4):330-41. PMID:16198652 doi:10.1016/j.clpt.2005.06.013