Elvitegravir

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The Investigational New Drug, Elvitegravir, (3l2u)

Better Known as: N/A

  • Marketed By: Gilead Sciences
  • Major Indication: Human Immunodeficiency Virus Infection
  • Drug Class: Retroviral Integrase Inhibitor
  • Expected FDA Approval: 2011
  • Projected 2013 Sales: $460 Million
  • Importance: It is expected to be the next effective HIV treatment to come to market. Expected to be the second Retroviral Integrase inhibitor approved. Currently in phase III clinical trials. Results from phase II trials indicate that the once-daily treatment was more effective than current HIV Protease inhibitor combinations.[1]
  • See Pharmaceutical Drugs for more information about other drugs and disorders.

Mechanism of Action

Retroviral Integrase is produced by the HIV retrovirus, enabling HIV to integrate its genetic material into the DNA of the infected cell. This integration step effectively transforms the infected cell into a permanent carrier of the viral genome, allowing the virus to persist and proliferate nearly without limit.[2] HIV retroviral integrase forms "intasomes" when it . The integrase domains interact extensively with the viral DNA, precisely within an active site, in close proximity to the predicted target DNA into which the viral DNA will be inserted. Elvitegravir binds with great specificity to the HIV integrase active site. It orients itself in such a way as to displace the reactive viral DNA end from the active site almost completely. to residues Asp 128, Asp 185, & Glu 221 via strong interactions with magnesium ions and has extensive π-stacking interactions with the final two nucleotide rings on one viral DNA strand. This disruption prevents the viral DNA from interacting with the target DNA, preventing integration and HIV proliferation.[3][4]

Pharmacokinetics

Retroviral Integrase Inhibitor Pharmacokinetics
Parameter Raltegravir Elvitegravir MK-2048
Tmax (hr) 1.8 2-4 N/A
Cmax (ng/ml) 4253 2070 N/A
Bioavailability (%) 32 ~30 N/A
Protein Binding (%) 83 N/A N/A
T1/2 (hr) 10.8 7.6 N/A
AUC (ng/ml/hr) 10168 21200 N/A
Dosage (mg) 400 150 N/A
Metabolism Hepatic - (UGT1A1) Hepatic - (CYP3A4) N/A

For Pharmacokinetic Data References, See: References

References

  1. Shimura K, Kodama E, Sakagami Y, Matsuzaki Y, Watanabe W, Yamataka K, Watanabe Y, Ohata Y, Doi S, Sato M, Kano M, Ikeda S, Matsuoka M. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J Virol. 2008 Jan;82(2):764-74. Epub 2007 Oct 31. PMID:17977962 doi:10.1128/JVI.01534-07
  2. Savarino A. A historical sketch of the discovery and development of HIV-1 integrase inhibitors. Expert Opin Investig Drugs. 2006 Dec;15(12):1507-22. PMID:17107277 doi:10.1517/13543784.15.12.1507
  3. Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature. 2010 Mar 11;464(7286):232-6. Epub 2010 Jan 31. PMID:20118915 doi:10.1038/nature08784
  4. Hare S, Vos AM, Clayton RF, Thuring JW, Cummings MD, Cherepanov P. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc Natl Acad Sci U S A. 2010 Oct 28. PMID:21030679 doi:10.1073/pnas.1010246107


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