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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: Phase III. A new drug application (NDA) for elvitegravir for treatment of HIV-1 infection in treatment-experienced adults was submitted to the U.S. Food and Drug Administration (FDA) in June 2012.
Chemical Image:
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elvitegravir
elvitegravir
Molecular Weight: 447.8877
(Compound details obtained from ChemIDplus Advanced1, NIAID Therapeutics Database2, and Gilead Sciences website3)

Pharmacology


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

: 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, E92G/Q, S147G, Q148R, and N155H, as determined by in vivo and 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


Elvitegravir is administered orally and once daily in combination with a boosting agent (CYP3A inhibitor) and with food.8

Phase III (treatment-experienced):

  • Ritonavir-boosted elvitegravir 150 mg (or a 85-mg dose if co-administered with atazanavir/ritonavir or lopinavir/ritonavir) versus raltegravir 400 mg twice daily, each in combination with a background regimen.8
Elvitegravir is also a component of an FDA-approved FDC tablet, Stribild.4 Additionally, elvitegravir is part of the investigational FDC tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.9


Adverse Events


In the Phase III study discussed in the Dosing section above (Study 145), the proportion of study subjects experiencing a serious adverse event, grade 3 or 4 adverse event, or study drug discontinuation due to an adverse event was similar in both treatment groups (elvitegravir versus raltegravir) through 96 weeks. Grade 3 or 4 AST and ALT elevations were more common in the raltegravir group than in the elvitegravir group.10 Through 48 weeks, diarrhea was reported more frequently in individuals assigned elvitegravir than raltegravir.11


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


References


1. United States National Library of Medicine. ChemIDplus Advanced.

2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development.

3. Gilead Sciences: Press Releases. Gilead Submits New Drug Application to U.S. FDA for HIV Integrase Inhibitor Elvitegravir for Treatment-Experienced Patients. Accessed May 15, 2013.

4. Gilead Sciences. Stribild: Full Prescribing Information, 2012. U.S. Food and Drug Administration website. Accessed May 15, 2013.

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.

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.

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.

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. Last accessed May 17, 2013.

9. 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-Naïve Adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 16, 2013. NLM Identifier: NCT01780506. Last accessed May 17, 2013.

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: 19th International AIDS Conference; July 22-27, 2012; Washington DC. Abstract TUAB0105.

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.


Last Reviewed: May 24, 2013

Last Updated: May 24, 2013