Rosiglitazone

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Rosiglitazone, also known as Avandia

Better Known as: Avandia

  • Marketed By: GlaxoSmithKline (No Longer Marketed)
  • Major Indication: Hypoglycemia & Type 2 Diabetes
  • Drug Class: PPAR-γ Agonist - Thiazolidinedione (Glitazones)
  • Date of FDA Approval (Patent Expiration): 1999 (2012)
  • 2009 (2006) Sales: $400 Million ($2.5 Billion)[1]
  • Importance: Once the best selling Diabetes treatment in the world. Lawsuits and legal action being pursued against GlaxoSmithKline for manipulation of clinical data upon which Avandia was approved with regards to its side effect profile.
  • See Pharmaceutical Drugs for more information about other drugs and disorders

Mechanism of Action

Rosiglitazone is a selective agonist for (PPAR). Unliganded PPAR forms a complex with various co-repressors which possess histone deacetylation activity, maintaining tight chromatin structure and preventing gene transcription. This complex is released upon ligand binding (typical ligands are lipids), allowing various co-activators and co-activator-associated proteins to be recruited. Rosiglitazone functions by by binding to the active site of PPARγ, causing the release of co-repressors and activation of the receptor. Activation of PPAR results in transcription of insulin responsive genes involved in the control of glucose production, transport and utilization. This explains why the glitazones are referred to as "insulin sensitizers." Rosiglitazone occupies roughly 40% of the LBD. It assumes a U-shaped conformation with the TZD head group that stabilize the agonist. Rosiglitazone forms hydrogen bond interactions with H323 and H449 and its TZD group, the sulfur atom of the TZD occupies a hydrophobic pocket formed by Phe363, Glu286, Phe282, Leu330, Ile326 and Leu469, and the central benzene ring occupies a pocket formed by Cys285 and Met364 [2]

Pharmacokinetics

Glitazone Pharmacokinetics Comparison at Equivalent Dosages
Parameter Pioglitazone (Actos) Rosiglitazone (Avandia)
Tmax (hr) 1.8 1
Cmax (ng/ml) 617 361
Bioavailability (%) 83 99
Protein Binding (%) 99 99
T1/2 (hr) 3-8 3-4
AUC (ng/ml/hr) 6244 2024
IC50 (nM) 360 10
Equivalent Dosage (mg) 30 4
Metabolism Hepatic
(CYP2C8)
Hepatic
(CYP2C8)

For Pharmacokinetic Data References, See: References

Effectiveness

Effectiveness

A number of clinical trials were conducted and validated that Rosiglitazone dramatically reduces Fasting plasma glucose (FPG), a measure of the concentration of glucose in the blood, as well as Glycalated Hemoglobin (HbA1c), a measure of average glucose concentration over a long period of time. At two 4mg doses per day, Rosiglitazone reduced FPG by 40.8 mg/dl compared to 30mg/dl with Glyburide (the state of the art medication at the time). Further, the rate of hypoglycemia among glyburide treated patients was 12.1% while only 1.6% among Rosiglitazone treated patients. When combined with Metformin (another hypoglycemia medication), 45% of patients had a greater than 30mg/dl FPG decrease from baseline while 46% had a greater than .7% decrease in HbA1c, compared to 20% and 11%, respectively, for Metformin alone. Similar results were observed when Rosiglitazone was combined with Sulfonylurea (a third hypoglycemia medication). Efficacy comparisons between Rosiglitazone and Pioglitazone revealed minimal differences at equivalent dosage levels. [3] [4]

References

  1. http://drugpatentwatch.com/ultimate/preview/tradename/index.php?query=AVANDIA
  2. Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature. 1998 Sep 10;395(6698):137-43. PMID:9744270 doi:10.1038/25931
  3. Norris SL, Carson S, Roberts C. Comparative effectiveness of pioglitazone and rosiglitazone in type 2 diabetes, prediabetes, and the metabolic syndrome: a meta-analysis. Curr Diabetes Rev. 2007 May;3(2):127-40. PMID:18220664
  4. Park JY, Kim KA, Kang MH, Kim SL, Shin JG. Effect of rifampin on the pharmacokinetics of rosiglitazone in healthy subjects. Clin Pharmacol Ther. 2004 Mar;75(3):157-62. PMID:15001966 doi:10.1016/j.clpt.2003.10.003


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