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FDA-approved

Investigational

Elvitegravir  Audio icon

Other Names: EVG, GS-9137, JTK-303
Drug Class: Integrase Inhibitors
Molecular Formula: C23 H23 Cl F N O5
Registry Number: 697761-98-1 (CAS)
Chemical Name: 6-[(3-chloro-2-fluoro-phenyl)methyl]-1-[(1S)-1-(hydroxymethyl)-2-methyl-propyl]-7-methoxy-4-oxo-quinoline-3-carboxylic acid
Chemical Class: Quinolines
Company: Japan Tobacco Inc.; Gilead Sciences; GlaxoSmithKline
Phase of Development: Elvitegravir has gone through Phase III testing in adults. A new drug application (NDA) for elvitegravir for the treatment of HIV infection in treatment-experienced adults was accepted by the Food and Drug Administration (FDA) in April 2014.
Chemical Image:
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elvitegravir
elvitegravir
Molecular Weight: 447.8877
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and Gilead Sciences, Inc. website3)
Patent Version Content

Pharmacology


Mechanism of Action: HIV-1 integrase strand transfer inhibitor. Elvitegravir prevents viral DNA integration into the host genome.4

Half-life (T½): Approximately 9.5 hours when boosted with either ritonavir or cobicistat.5

Metabolism/Elimination: Elvitegravir is primarily metabolized by cytochrome P450 (CYP) 3A4/5 and partly by glucuronidation via UGT1A1/3.6 Following single-dose administration of radiolabeled elvitegravir with ritonavir, 94.8% of the administered dose was recovered in feces and 6.7% was recovered in urine.4,6

Resistance: Primary resistance-conferring mutations associated with elvitegravir include T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, and N155H, as determined by in vivo and/or in vitro cell culture studies.4,6,7 Among primary raltegravir resistance-associated substitutions (Y143H/R, Q148H/K/R, and N155H), all, with the exception of one (Y143H), confer reduced susceptibility to elvitegravir in vivo.4


Dosing in Clinical Trials


Study Identifiers: GS-US-183-0145; Study 145; NCT007081628
Phase: III
Study Purpose: Safety and efficacy study of ritonavir-boosted elvitegravir (EVG/r) versus raltegravir (RAL)
Study Population: HIV-infected, treatment-experienced adults with documented resistance or at least 6 months of experience with two or more different antiretroviral (ARV) drug classes
Dosing: EVG/r 150 mg (or 85 mg if co-administered with atazanavir/ritonavir or lopinavir/ritonavir) administered orally and once daily with food versus RAL 400 mg given twice daily, each in combination with a ritonavir-boosted protease inhibitor and a third ARV agent8-11
(See references cited above for information on study results.)

EVG/r is also being investigated in HIV-infected, treatment-experienced pediatric patients.12 

Elvitegravir is a component of an FDA-approved fixed-dose combination (FDC) tablet, Stribild.4 Additionally, elvitegravir is part of the investigational FDC tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.13


Adverse Events


In the Phase III study discussed in the Dosing section above (Study 145), the proportion of study participants experiencing a serious adverse event, a Grade 3 or 4 adverse event, or a study drug discontinuation due to an adverse event was similar in both treatment groups (elvitegravir versus raltegravir) through 96 weeks. Grade 3 or 4 aspartate aminotransferase (AST) and alanine transaminase (ALT) elevations were more common in the raltegravir group than in the elvitegravir group.10 Out of the common Grade 2 to 4 adverse events reported, diarrhea was the only one that was significantly more frequent in the elvitegravir group than in the raltegravir group.9


Drug Interactions


Elvitegravir is metabolized by CYP3A enzymes. Drugs that induce CYP3A activity may increase the clearance of elvitegravir. Elvitegravir is a modest CYP2C9 inducer and may decrease plasma concentrations of known CYP2C9 substrates.4 Multiple drug-drug interactions are likely to exist between elvitegravir (boosted with ritonavir) and other co-administered agents. Some drugs that may interact with elvitegravir include atazanavir, lopinavir/ritonavir, maraviroc, rifabutin, ketoconazole, norgestimate and ethinyl estradiol, and antacids.6 Other significant drug interactions related to elvitegravir have been described in the Stribild full prescribing label and in the European Public Assessment Report (EPAR) for Vitekta. (Elvitegravir is approved in Europe under the brand name Vitekta.)4,14


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/697761-98-1. Last accessed on August 20, 2014.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on August 20, 2014.
  3. Gilead Sciences, Inc.: Press Release, dated April 21, 2014. Gilead Sciences’ New Drug Applications for Cobicistat and Elvitegravir for HIV Therapy Accepted by U.S. FDA. Available at: http://www.gilead.com/news/press-releases/2014/4/gilead-sciences-new-drug-applications-for-cobicistat-and-elvitegravir-for-hiv-therapy-accepted-by-us-fda. Last accessed on August 20, 2014.
  4. Gilead Sciences, Inc. Stribild: Full Prescribing Information, 2013. DailyMed. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=74ae2a93-b267-444c-8f0f-a2a6522260ee. Last accessed on August 20, 2014.
  5. Ramanathan S, Mathias AA, German P, Kearney BP. Clinical pharmacokinetic and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin Pharmacokinet. 2011 Apr;50(4):229-44. http://www.ncbi.nlm.nih.gov/pubmed/21348537. Last accessed on August 20, 2014.
  6. Lee JS, Calmy A, Andrieux-Meyer I, Ford N. Review of the safety, efficacy, and pharmacokinetics of elvitegravir with an emphasis on resource-limited settings. HIV AIDS (Auckl). 2012;4:5-15. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280623/. Last accessed on August 20, 2014.
  7. McColl DJ, Fransen S, Gupta S, et al. Resistance and cross-resistance to first generation integrase inhibitors: insights from a Phase II study of elvitegravir (GS-9137). Abstract presented at: 16th International HIV Drug Resistance Workshop: Basic Principles & Clinical Implications; June 12-16, 2007; Barbados, West Indies. Abstract 9. Available at: http://www.intmedpress.com/serveFile.cfm?sUID=36a5d521-cb5c-4d51-9490-936bf008c2c3. Last accessed on August 20, 2014.
  8. Gilead Sciences. A Multicenter, Randomized, Double-Blind, Double-Dummy, Phase 3 Study of the Safety and Efficacy of Ritonavir-Boosted Elvitegravir (EVG/r) Versus Raltegravir (RAL) Each Administered With a Background Regimen in HIV-1 Infected, Antiretroviral Treatment-Experienced Adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 30, 2008. NLM Identifier: NCT00708162. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00708162. Last accessed on August 20, 2014.
  9. Elion R, Molina JM, Arribas-Lopez JR, et al. Efficacy and Safety Results from a Randomized, Double-Blind, Active-Controlled Trial of Elvitegravir (Once-Daily) vs. Raltegravir (Twice-Daily) in Treatment-Experienced HIV-Infected Patients: Long Term 96-Week Data. 19th International AIDS Conference; July 22-27, 2012; Washington DC. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2012. Available at: http://www.natap.org/2012/IAS/IAS_03.htm. Last accessed on August 20, 2014.
  10. Elion R, Molina JM, Arribas-Lopez JR, et al. Efficacy and safety results from a randomized, double blind, active controlled trial of elvitegravir (once-daily) versus raltegravir (twice-daily) in treatment-experienced HIV-positive patients: long term 96-week data. Abstract presented at: 19thInternational AIDS Conference; July 22-27, 2012; Washington DC. Abstract TUAB0105. Available at: http://pag.aids2012.org/abstracts.aspx?aid=5823. Last accessed on August 20, 2014.
  11. Molina JM, Lamarca A, Andrade-Villanueva J, et al. Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study. Lancet Infect Dis. 2012 Jan;12(1):27-35. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22015077.1. Last accessed on August 20, 2014.
  12. Gilead Sciences. A Phase 2/3 Multicenter, Open-Label, Multicohort, Two-Part Study Evaluating the Pharmacokinetics (PK), Safety, and Antiviral Activity of Elvitegravir (EVG) Administered With a Background-Regimen (BR) Containing a Ritonavir-Boosted Protease Inhibitor (PI/r) in HIV-1 Infected, Antiretroviral Treatment-Experienced Pediatric Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 9, 2013. NLM Identifier: NCT01923311. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01923311. Last accessed on August 20, 2014.
  13. Gilead Sciences. A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Versus Elvitegravir/Cobicistat/Emtricitabine/ Tenofovir Disoproxil Fumarate in HIV-1 Positive, Antiretroviral Treatment-Naive Adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 16, 2013. NLM Identifier: NCT01780506. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01780506. Last accessed on August 20, 2014.
  14. Gilead Sciences International Limited. Vitekta: European Public Assessment Report, 2014. European Medicines Agency. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002577/WC500155576.pdf. Last accessed on August 20, 2014.
 


Last Reviewed: August 20, 2014

Last Updated: August 20, 2014


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