Elvitegravir: Difference between revisions

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{{Short description|Chemical compound}}
{{drugbox
{{Infobox drug
| Verifiedfields = changed
| Verifiedfields = changed
| UNII_Ref = {{fdacite|changed|FDA}}
| Watchedfields = changed
| verifiedrevid = 437144022
| UNII = 4GDQ854U53
| image = Elvitegravir structure.svg
| verifiedrevid = 422845789
| image2 = Elvitegravir3D.PNG
| IUPAC_name = 6-[(3-Chloro-2-fluorophenyl)methyl]-1-[(2''S'')-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxoquinoline-3-carboxylic acid

| image = Elvitegravir.png
<!--Clinical data-->
|image2 = Elvitegravir3D.PNG
| tradename = Vitekta; [[Stribild]] (fixed-dose combination)
| licence_EU = yes
| routes_of_administration = [[Oral administration|By mouth]]
| ATC_prefix = J05
| ATC_suffix = AJ02

| legal_UK =
| legal_US =
| legal_status =

<!--Pharmacokinetic data-->
| bioavailability =
| protein_bound = 98%
| metabolism = liver, via [[CYP3A]]
| elimination_half-life = 12.9 (8.7–13.7) hours
| excretion = liver 93%, renal 7%

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 697761-98-1
| PubChem = 5277135
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4441060
| ChemSpiderID = 4441060
| UNII_Ref = {{fdacite|correct|FDA}}
| InChI = 1/C23H23ClFNO5/c1-12(2)19(11-27)26-10-16(23(29)30)22(28)15-8-14(20(31-3)9-18(15)26)7-13-5-4-6-17(24)21(13)25/h4-6,8-10,12,19,27H,7,11H2,1-3H3,(H,29,30)/t19-/m1/s1
| UNII = 4GDQ854U53
| InChIKey = JUZYLCPPVHEVSV-LJQANCHMBZ
| ChEBI_Ref = {{ebicite|changed|EBI}}
| smiles = Clc1cccc(c1F)Cc3c(OC)cc2c(C(=O)\C(=C/N2[C@H](CO)C(C)C)C(=O)O)c3
| ChEBI = 72289
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 204656
| ChEMBL = 204656
| NIAID_ChemDB = 241767
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = D06677
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB09101
| synonyms = GS-9137

<!--Chemical data-->
| IUPAC_name = 6-[(3-Chloro-2-fluorophenyl)methyl]-1-[(2''S'')-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxoquinoline-3-carboxylic acid
| C=23 | H=23 | Cl=1 | F=1 | N=1 | O=5
| smiles = Clc1cccc(c1F)Cc3c(OC)cc2c(C(=O)\C(=C/N2[C@H](CO)C(C)C)C(=O)O)c3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C23H23ClFNO5/c1-12(2)19(11-27)26-10-16(23(29)30)22(28)15-8-14(20(31-3)9-18(15)26)7-13-5-4-6-17(24)21(13)25/h4-6,8-10,12,19,27H,7,11H2,1-3H3,(H,29,30)/t19-/m1/s1
| StdInChI = 1S/C23H23ClFNO5/c1-12(2)19(11-27)26-10-16(23(29)30)22(28)15-8-14(20(31-3)9-18(15)26)7-13-5-4-6-17(24)21(13)25/h4-6,8-10,12,19,27H,7,11H2,1-3H3,(H,29,30)/t19-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = JUZYLCPPVHEVSV-LJQANCHMSA-N
| StdInChIKey = JUZYLCPPVHEVSV-LJQANCHMSA-N
| CAS_number = 697761-98-1
| ATC_prefix = none
| ATC_suffix =
| PubChem = 5277135
| C=23 | H=23 | Cl=1 | F=1 | N=1 | O=5
| molecular_weight = 447.883 g/mol
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| excretion =
| pregnancy_US =
| legal_UK =
| legal_US =
| legal_status =
| routes_of_administration =
}}
}}


'''Elvitegravir''' (EVG) is an [[investigational new drug]] for the treatment of [[HIV]] infection. It acts as an [[integrase inhibitor]]. It is undergoing Phase III [[clinical trial]]<ref>Gilead Press Release [http://www.gilead.com/pr_1177855 Phase III Clinical Trial of Elvitegravir] July 22, 2008</ref> conducted by the pharmaceutical company [[Gilead Sciences]], which licensed EVG from [[Japan Tobacco]] in March 2008.<ref>Gilead Press Release [http://www.gilead.com/pr_687733 Gilead and Japan Tobacco Sign Licensing Agreement for Novel HIV Integrase Inhibitor] March 22, 2008</ref><ref>{{cite journal |author=Shimura K, Kodama E, Sakagami Y, ''et al.'' |title=Broad Anti-Retroviral Activity and Resistance Profile of a Novel Human Immunodeficiency Virus Integrase Inhibitor, Elvitegravir (JTK-303/GS-9137) |journal=J Virol |volume= 82|issue= 2|pages= 764|year=2007 |pmid=17977962 |doi=10.1128/JVI.01534-07 |url=http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=17977962 |pmc=2224569}}</ref><ref>{{cite journal |author=Stellbrink HJ |title=Antiviral drugs in the treatment of AIDS: what is in the pipeline ? |journal=Eur. J. Med. Res. |volume=12 |issue=9 |pages=483–95 |year=2007 |pmid=17933730 |doi=}}</ref>
'''Elvitegravir''' ('''EVG''') is an [[integrase inhibitor]] used to treat [[HIV]] infection. It was developed<ref>{{cite web | work = Gilead Press Release | url = http://www.gilead.com/pr_1177855 | title = Phase III Clinical Trial of Elvitegravir | archive-url = https://web.archive.org/web/20130208062306/http://www.gilead.com/pr_1177855 | archive-date=2013-02-08 | date = 22 July 2008 }}</ref> by the pharmaceutical company [[Gilead Sciences]], which licensed EVG from [[Japan Tobacco]] in March 2008.<ref>{{cite web | work = Gilead Press Release | url = http://www.gilead.com/pr_687733 | title = Gilead and Japan Tobacco Sign Licensing Agreement for Novel HIV Integrase Inhibitor | archive-url = https://web.archive.org/web/20130208133209/http://www.gilead.com/pr_687733 | archive-date=2013-02-08 | date = March 22, 2008 }}</ref><ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137) | journal = Journal of Virology | volume = 82 | issue = 2 | pages = 764–774 | date = January 2008 | pmid = 17977962 | pmc = 2224569 | doi = 10.1128/JVI.01534-07 }}</ref><ref>{{cite journal | vauthors = Stellbrink HJ | title = Antiviral drugs in the treatment of AIDS: what is in the pipeline ? | journal = European Journal of Medical Research | volume = 12 | issue = 9 | pages = 483–495 | date = October 2007 | pmid = 17933730 }}</ref> The drug gained approval by the U.S. [[Food and Drug Administration]] on August 27, 2012, for use in adult patients starting HIV treatment for the first time as part of the [[fixed dose combination]] known as [[Stribild]].<ref>{{cite journal | vauthors = Sax PE, DeJesus E, Mills A, Zolopa A, Cohen C, Wohl D, Gallant JE, Liu HC, Zhong L, Yale K, White K, Kearney BP, Szwarcberg J, Quirk E, Cheng AK | display-authors = 6 | title = Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks | journal = Lancet | volume = 379 | issue = 9835 | pages = 2439–2448 | date = June 2012 | pmid = 22748591 | doi = 10.1016/S0140-6736(12)60917-9 | s2cid = 24183976 }}</ref> On September 24, 2014, the FDA approved Elvitegravir as a single pill formulation under the trade name '''Vitekta'''.<ref>{{cite web | url = http://content.govdelivery.com/accounts/USFDA/bulletins/d162bb | title = FDA Approval Bulletin | archive-url = https://web.archive.org/web/20141103062906/http://content.govdelivery.com/accounts/USFDA/bulletins/d162bb | archive-date=2014-11-03 }}</ref> On November 5, 2015, the FDA approved the drug for use in patients affected with HIV-1 as a part of a second fixed dose combination pill known as [[Genvoya]].<ref>{{Cite web|title = Press Announcements - FDA approves new treatment for HIV|url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm471300.htm|website = www.fda.gov|access-date = 2016-01-10|language = en}}</ref>


According to the results of the phase II clinical trial, patients taking once-daily elvitegravir boosted by [[ritonavir]] had greater reductions in [[viral load]] after 24 weeks compared to individuals randomized to receive a ritonavir-boosted [[protease inhibitor]].<ref>Thaczuk, Derek and Carter, Micheal. [http://www.aidsmap.com/en/news/69FAE9A0-307D-430B-8023-DA133AD0CEDB.asp ICAAC: Best response to elvitegravir seen when used with T-20 and other active agents] Aidsmap.com. 19 Sept. 2007.</ref>
According to the results of the phase II clinical trial, patients taking once-daily elvitegravir boosted by [[ritonavir]] had greater reductions in [[viral load]] after 24 weeks compared to individuals [[Randomized controlled trial|randomized]] to receive a ritonavir-boosted [[Protease inhibitor (pharmacology)|protease inhibitor]].<ref>{{cite web | vauthors = Thaczuk D, Carter M | url = https://www.aidsmap.com/news/sep-2007/icaac-best-response-elvitegravir-seen-when-used-t-20-and-other-active-agents | title = ICAAC: Best response to elvitegravir seen when used with T-20 and other active agents | archive-url = https://web.archive.org/web/20100102230214/http://aidsmap.com/en/news/69FAE9A0-307D-430B-8023-DA133AD0CEDB.asp | archive-date=2010-01-02 | work = Aidsmap.com | date = 19 September 2007 }}</ref>


==References==
==Medical uses==
In the United States, elvitegravir can be obtained either as part of the combination pills [[Stribild]] or [[Genvoya]], or as the single pill formulation Vitekta.<ref>{{cite web | url = http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm | title = FDA Approved Drug Listing | access-date = March 3, 2017 }}</ref>

Vitekta is [[FDA]] approved to be used for the treatment of HIV-1 infection in adults who have previous treatment experience with [[antiretroviral therapy]]. It must be used in combination with a protease inhibitor that is coadministered with [[ritonavir]] as well as additional antiretroviral drug(s).<ref name = "PI">{{cite web | url = http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=be87c3bc-97bb-49cb-8053-9b0c756a1965#section-1 | title = Vitekta Package Insert | location = Foster City, CA | publisher = Gilead Sciences, Inc. | date = 2014 | access-date = November 1, 2014 | via = U.S. Food and Drug Administration }}</ref>

==Adverse effects==
The most common side effects of taking elvitegravir are [[diarrhea]] (in 7% of patients) and [[nausea]] (4%). Other side effects that occurred in more than 1% of people are [[headache]], [[Fatigue|tiredness]], [[rashes]], and [[vomiting]].<ref name = "PI" /><ref name="AC">{{cite book|title=Austria-Codex| veditors = Haberfeld H|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2015|language=de}}</ref>

==Interactions and contraindications==
Elvitegravir is metabolised via the liver enzyme [[CYP3A]]. Substances that induce this enzyme can reduce elvitegravir concentrations in the body, potentially triggering the development of [[Drug resistance|resistant]] virus strains. Consequently, co-administration of strong CYP3A inducers is contraindicated; examples are [[rifampicin]], the anticonvulsants [[carbamazepine]], [[phenobarbital]] and [[phenytoin]], as well as [[St John's wort]].<ref name="AC" />

[[Glucuronidation]] of elvitegravir is facilitated by the enzymes [[UGT1A1]] and [[UGT1A3|3]], resulting in increased blood plasma levels when taken together with strong UGT1A inhibitors such as [[ritonavir]] and other [[HIV protease inhibitor]]s.<ref name="AC" /><ref>{{cite journal | vauthors = Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS, Humphreys WG | title = In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation | journal = Drug Metabolism and Disposition | volume = 33 | issue = 11 | pages = 1729–1739 | date = November 2005 | pmid = 16118329 | doi = 10.1124/dmd.105.005447 | s2cid = 1964934 }}</ref> (But ritonavir also increases elvitegravir levels by inhibiting CYP3A.)

Furthermore, elvitegravir is a weak to medium inducer of [[CYP1A2]], [[CYP2C19]], [[CYP2C9]], CYP3A, and a number of [[Glucuronosyltransferase|UGT]]s; the clinical relevance of these findings is however unclear.<ref name="AC" />

==Pharmacology==
===Mechanism of action===
Elvitegravir inhibits the enzyme [[integrase]] of [[HIV-1]], and of HIV-2 to a lesser extent. The virus needs this enzyme to integrate its genetic code into the host's [[DNA]].<ref name="AC" />

===Pharmacokinetics===
The drug is taken by mouth. When taken together with ritonavir and a meal, it reaches highest blood plasma concentrations after four hours. [[Bioavailability]] is better with fatty meals. In the bloodstream, 98–99% of the substance are bound to [[plasma protein]]s. It is metabolized mainly by CYP3A oxidation, and secondly by UGT1A1 and 3 glucuronidation. Nearly 95% are excreted via the feces, and the rest via urine. [[Plasma half-life]] when combined with ritonavir is 8.7 to 13.7 hours.<ref name="AC" />

== References ==
{{reflist}}
{{reflist}}


== External links ==
{{HIVpharm}}
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/elvitegravir | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Elvitegravir }}

{{Antiretroviral drug}}
{{Portal bar | Medicine | Viruses }}


[[Category:Integrase inhibitors]]
[[Category:Integrase inhibitors]]
[[Category:Quinolines]]
[[Category:Quinolines]]
[[Category:Organochlorides]]
[[Category:Chloroarenes]]
[[Category:Organofluorides]]
[[Category:Fluoroarenes]]
[[Category:Japan Tobacco]]

{{antiinfective-agent-stub}}

[[fr:Elvitégravir]]
[[pt:Elvitegravir]]
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