Elvitegravir

Elvitegravir (EVG) is an integrase inhibitor used to treat HIV infection. It was developed[1] by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008.[2][3][4] 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.[5] On September 24, 2014 the FDA approved Elvitegravir as a single pill formulation under the trade name Vitekta.[6] 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.[7]

Elvitegravir
Clinical data
Trade namesVitekta; Stribild (fixed-dose combination)
Other namesGS-9137
License data
Routes of
administration		By mouth
ATC code
Pharmacokinetic data
Protein binding98%
Metabolismliver, via CYP3A
Elimination half-life12.9 (8.7–13.7) hours
Excretionliver 93%, renal 7%
Identifiers
  • 6-[(3-Chloro-2-fluorophenyl)methyl]-1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxoquinoline-3-carboxylic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
Chemical and physical data
FormulaC23H23ClFNO5
Molar mass447.89 g·mol−1
3D model (JSmol)
  • Clc1cccc(c1F)Cc3c(OC)cc2c(C(=O)\C(=C/N2[C@H](CO)C(C)C)C(=O)O)c3
  • InChI=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 checkY
  • Key:JUZYLCPPVHEVSV-LJQANCHMSA-N checkY
 ☒NcheckY (what is this?)  (verify)

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.[8]

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.[9]

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).[10]

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, tiredness, rashes, and vomiting.[10][11]

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 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.[11]

Glucuronidation of elvitegravir is facilitated by the enzymes UGT1A1 and 3, resulting in increased blood plasma levels when taken together with strong UGT1A inhibitors such as ritonavir and other HIV protease inhibitors.[11][12] (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 UGTs; the clinical relevance of these findings is however unclear.[11]

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.[11]

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 proteins. 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.[11]

References
  1. "Phase III Clinical Trial of Elvitegravir". Gilead Press Release. 22 July 2008. Archived from the original on 2013-02-08.
  2. "Gilead and Japan Tobacco Sign Licensing Agreement for Novel HIV Integrase Inhibitor". Gilead Press Release. March 22, 2008. Archived from the original on 2013-02-08.
  3. Shimura K, Kodama E, Sakagami Y, Matsuzaki Y, Watanabe W, Yamataka K, et al. (January 2008). "Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137)". Journal of Virology. 82 (2): 764–774. doi:10.1128/JVI.01534-07. PMC 2224569. PMID 17977962.
  4. Stellbrink HJ (October 2007). "Antiviral drugs in the treatment of AIDS: what is in the pipeline ?". European Journal of Medical Research. 12 (9): 483–495. PMID 17933730.
  5. Sax PE, DeJesus E, Mills A, Zolopa A, Cohen C, Wohl D, et al. (June 2012). "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". Lancet. 379 (9835): 2439–2448. doi:10.1016/S0140-6736(12)60917-9. PMID 22748591. S2CID 24183976.
  6. "FDA Approval Bulletin". Archived from the original on 2014-11-03.
  7. "Press Announcements - FDA approves new treatment for HIV". www.fda.gov. Retrieved 2016-01-10.
  8. Thaczuk D, Carter M (19 September 2007). "ICAAC: Best response to elvitegravir seen when used with T-20 and other active agents". Aidsmap.com. Archived from the original on 2010-01-02.
  9. "FDA Approved Drug Listing". Retrieved March 3, 2017.
  10. "Vitekta Package Insert". Foster City, CA: Gilead Sciences, Inc. 2014. Retrieved November 1, 2014 – via U.S. Food and Drug Administration.
  11. Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  12. Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS, Humphreys WG (November 2005). "In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation". Drug Metabolism and Disposition. 33 (11): 1729–1739. doi:10.1124/dmd.105.005447. PMID 16118329. S2CID 1964934.
  • "Elvitegravir". Drug Information Portal. U.S. National Library of Medicine.
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