Elvitegravir
From Proteopedia
(Difference between revisions)
| Line 10: | Line 10: | ||
===Mechanism of Action=== | ===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 extensively.<ref>PMID:17107277</ref> HIV retroviral integrase forms "intasomes" when it <scene name=' | + | [[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 extensively.<ref>PMID:17107277</ref> HIV retroviral integrase forms "intasomes" when it <scene name='Elvitegravir/Full/1'>complexes with viral DNA</scene>. The integrase domains interact extensively with the viral DNA, <scene name='Elvitegravir/Tight/1'>binding the nucleotide chains</scene> precisely within an active site, in close proximity to the predicted target DNA into which the viral DNA will be inserted. Raltegravir 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. <scene name='_'>Raltegravir binds</scene> to residues Asp 128, Asp 185, & Glu 221 via hydrogen bonds, has extensive π-stacking interactions with residues Tyr 212, Pro 214 and 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.<ref>doi: 10.1038/nature08784</ref> |
===Pharmacokinetics=== | ===Pharmacokinetics=== | ||
Revision as of 08:44, 8 December 2010
|
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]
- The following is a list of Pharmacokinetic Parameters. See: Pharmaceutical Drugs for more information
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 extensively.[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. Raltegravir 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 hydrogen bonds, has extensive π-stacking interactions with residues Tyr 212, Pro 214 and 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]
Pharmacokinetics
| Retroviral Integrase Inhibitor Pharmacokinetics[4][5] | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Parameter | Raltegravir | Elvitegravir | |||||||||
| Tmax (hr) | 1.8 | 2-4 | |||||||||
| Cmax (ng/ml) | 4253 | 2070 | |||||||||
| Bioavailability (%) | 32 | ~30 | |||||||||
| Protein Binding (%) | 83 | N/A | |||||||||
| T1/2 (hr) | 10.8 | 7.6 | |||||||||
| AUC (ng/ml/hr) | 10168 | 21200 | |||||||||
| Dosage (mg) | 400 | 150 | |||||||||
| Metabolism | Hepatic - (UGT1A1) | Hepatic - (CYP3A4) | |||||||||
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ A Gaur, et al. Pharmacokinetics and Safety of Once-Daily Elvitegravir in HIV-Infected Adolescents. 17th Conference on Retroviruses. Poster Number: 874.
- ↑ Iwamoto M, Wenning LA, Petry AS, Laethem M, De Smet M, Kost JT, Breidinger SA, Mangin EC, Azrolan N, Greenberg HE, Haazen W, Stone JA, Gottesdiener KM, Wagner JA. Minimal effects of ritonavir and efavirenz on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother. 2008 Dec;52(12):4338-43. Epub 2008 Oct 6. PMID:18838589 doi:10.1128/AAC.01543-07
