Elvitegravir (GS-9137, JTK-303) targets HIV-1 integrase (IC50 = 0.79 nM for wild-type HIV-1 integrase strand transfer reaction; Ki = 0.41 nM) [1]
Elvitegravir (GS-9137, JTK-303) inhibits wild-type HIV-1 replication in human PBMCs with an EC50 of 0.028 μM; EC50 values for integrase mutant strains: N155H (0.12 μM), Q148K (0.31 μM), G140S/Q148H (0.58 μM) [1]
Elvitegravir (GS-9137, JTK-303) exhibits activity against HIV-2 replication in human PBMCs with an EC50 of 0.063 μM [1]

Elvitegravir (GS-9137; JTK-303; D06677) inhibits DNA strand transfer, which prevents HIV-1 cDNA integration. Elvitegravir exhibits strong anti-HIV properties against both drug-resistant clinical isolates and wild-type strains. Fascinatingly, elevategravir also demonstrates antiviral action against the simian immunodeficiency virus (SIV) and the murine leukemia virus (MLV). Three laboratory strains of HIV were effectively inhibited by elvitegravir, with EC50 values ranging from subnanomolar to nanomolar. Subsequently, Elvitegravir's efficacy was assessed in comparison to clinical isolates of wild-type HIV-1 subtypes. All HIV-1 subtypes examined with antiviral EC50s ranging from 0.1 to 1.26 nM are inhibited by elevategravir in terms of replication. Additionally, both elvitegravir and the control IN inhibitor drug L-870,810 prevented the replication of HIV-1 clinical isolates with genotypes linked to PI resistance, NRTI, and NNRTI. The MTT colorimetric test was also used to assess the cytotoxicity of these inhibitors. The average values of L-870,810 and Elvitegravir that reduced target cell viability by 50% in PBMC derived from three different donors were 2.7±0.6 μM and 4.6±0.5 μM, respectively. Elvitegravir thus suppresses a variety of HIV strains, including clinical isolates with numerous alterations linked to resistance to presently licensed antiretroviral medications and a number of HIV-1 subtypes [1].

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Elvitegravir (GS-9137, JTK-303) potently inhibited HIV-1 integrase-mediated strand transfer reaction, blocking viral DNA integration into host genome with 90% inhibition at 2 nM [1]
Elvitegravir (GS-9137, JTK-303) showed broad-spectrum antiviral activity against 18 HIV-1 clinical isolates (including subtype B, C, D, AE) with EC50 values ranging from 0.019 to 0.045 μM [1]
Elvitegravir (GS-9137, JTK-303) exhibited synergistic antiviral activity with NRTIs (tenofovir, emtricitabine) and NNRTIs (efavirenz) in HIV-1-infected PBMCs, with combination indices (CI) of 0.72, 0.68, and 0.75 respectively [1]
Elvitegravir (GS-9137, JTK-303) had low cytotoxicity in human PBMCs, MT-4, and HeLa cells, with CC50 values > 10 μM, resulting in a selectivity index (SI) > 357 for wild-type HIV-1 [1]
Elvitegravir (GS-9137, JTK-303) bound to the HIV-1 integrase catalytic core domain, stabilizing the integrase-DNA complex and preventing the strand transfer step of viral integration [1]
Elvitegravir (GS-9137, JTK-303) showed reduced activity against HIV-1 strains with integrase mutations E92Q (EC50 = 0.15 μM) and T66I (EC50 = 0.23 μM) but remained active compared to first-generation INSTIs [1]

HIV-1 integrase strand transfer inhibition assay: Prepare a reaction mixture containing recombinant HIV-1 integrase catalytic core, preprocessed viral DNA substrate (donor DNA), and target DNA. Incubate with serial dilutions of Elvitegravir (GS-9137, JTK-303) (0.01–10 nM) at 37°C for 60 min. Separate reaction products by 10% polyacrylamide gel electrophoresis, stain with ethidium bromide, and quantify the intensity of the strand transfer product band to calculate IC50 [1]
HIV-1 integrase binding affinity assay: Immobilize purified HIV-1 integrase on a sensor chip. Inject serial concentrations of Elvitegravir (GS-9137, JTK-303) in the presence of Mg²+ (10 mM) at 25°C. Monitor changes in refractive index using surface plasmon resonance (SPR) to determine the dissociation constant (Ki) [1]

HIV-1 antiviral cell assay: Seed human PBMCs, MT-4, or HeLa cells in 96-well plates at 2×105 cells/well. Infect with wild-type or mutant HIV-1 strains (MOI = 0.01) and add Elvitegravir (GS-9137, JTK-303) at concentrations ranging from 0.001 to 10 μM. Incubate for 7 days, then measure viral p24 antigen levels by ELISA to calculate EC50 [1]
Synergistic antiviral cell assay: Treat HIV-1-infected PBMCs with Elvitegravir (GS-9137, JTK-303) in combination with tenofovir (0.1–1 μM), emtricitabine (0.1–1 μM), or efavirenz (0.01–0.1 μM) at various concentration ratios. Calculate EC50 values for each drug alone and in combination, then determine combination indices (CI) using the Chou-Talalay method [1]
Cell cytotoxicity assay: Culture human PBMCs, MT-4, and HeLa cells in 96-well plates with Elvitegravir (GS-9137, JTK-303) (0.1–100 μM) for 7 days. Assess cell viability using MTT assay and calculate CC50 and selectivity index (SI = CC50/EC50) [1]

Absorption, Distribution and Excretion
In HIV-1 infected individuals, after oral administration of avigravir and ritonavir (with food), peak plasma concentrations of avigravir occur approximately 4 hours after administration. Following oral administration of [14C]avigravir/ritonavir, 94.8% of the dose is excreted in feces, and 6.7% is excreted in urine as metabolites. Metabolism/Metabolites Avigravir is primarily metabolized via oxidative metabolism through CYP3A, followed by glucuronidation via UGT1A1/3 enzymes. Metabolites are present in very low plasma concentrations, exhibit significantly lower anti-HIV activity, and do not contribute to the overall antiviral activity of avigravir. Biological Half-Life The median terminal plasma half-life after administration of avigravir and ritonavir is approximately 8.7 hours.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no publicly available information regarding the use of avigravir during lactation. Alternative medications are recommended. Achieving and maintaining viral suppression through antiretroviral therapy can reduce the risk of transmission through breastfeeding to below 1%, but not zero. This decision should be supported for HIV-infected individuals receiving antiretroviral therapy with a persistently low viral load who choose to breastfeed. If viral load is not suppressed, pasteurized donor breast milk or formula is recommended.
◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
Gynecomastia has been reported in men receiving highly active antiretroviral therapy. Gynecomastia is initially unilateral, but approximately half of cases progress to bilateral gynecomastia. No changes in serum prolactin levels have been observed, and symptoms usually resolve spontaneously within one year even with continued medication. Some case reports and in vitro studies have shown that protease inhibitors may cause hyperprolactinemia and galactorrhea in some male patients, but this conclusion remains controversial. The implications of these findings for lactating women are unclear. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.

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Protein binding
Elvigravir binds to human plasma proteins at a rate of 98-99%.

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Elvigravir (GS-9137, JTK-303) did not show significant cytotoxicity to normal human cells (PBMC, HeLa) at concentrations up to 10 μM[1].
Elvigravir (GS-9137, JTK-303) had CC50 values of >10 μM, >20 μM, and >10 μM in MT-4, HeLa, and human PBMC, respectively[1].

[1]. Shimura K, et al. 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

Elvitegravir is a quinoline monocarboxylic acid with the structure 7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, where 1-position is substituted with a 1-hydroxy-3-methylbut-2-yl group and 6-position with a 3-chloro-2-fluorobenzyl group (S-enantiomer). It is used in combination therapy for HIV-1 infection. It is an HIV-1 integrase inhibitor. It is a quinoline monocarboxylic acid, an organofluorine compound, an aromatic ether, a quinolone compound, and also belongs to the monochlorobenzene class of compounds. Elvitegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) used to treat adults with HIV-1 infection who have previously received antiretroviral therapy. Because integrase is essential for viral replication, inhibiting integrase prevents HIV-1 DNA from integrating into the host genome, thereby blocking the formation of HIV-1 provirus and the resulting transmission of viral infection. Although avigravir is available in single-dose tablet form, it must be used in combination with an HIV protease inhibitor and concurrently with ritonavir and another antiretroviral drug. Avigravir was first licensed from Japan Tobacco in 2008 and developed by Gilead Sciences. It was approved by the U.S. Food and Drug Administration (FDA) on August 27, 2012. On September 24, 2014, the FDA approved the single-dose tablet form of avigravir. Avigravir is a human immunodeficiency virus integrase chain transfer inhibitor. Its mechanism of action is as an HIV integrase inhibitor and cytochrome P450 2C9 inducer. Avigravir is a modified quinolone antibiotic active against human immunodeficiency virus type 1 (HIV-1). Avigravir is a viral integrase inhibitor and remains effective against raltegravir-resistant integrase mutants.
See also: ...See more...

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Drug Indications
Elvigravir, in combination with an HIV protease inhibitor (in combination with ritonavir) and other antiretroviral agents, is indicated for the treatment of HIV-1 infection in adults who have previously received antiretroviral therapy.
FDA Label
Elvigravir (Vitekta), in combination with a ritonavir-enhanced protease inhibitor and other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. It is indicated for the treatment of HIV-1 infection in adults who do not carry mutations known to be associated with elvigravir resistance.
Treatment of Human Immunodeficiency Virus (HIV-1) Infection

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Mechanism of Action
Elvigravir is an HIV-1 integrase strand transfer inhibitor (INSTI). Integrase is an enzyme encoded by HIV-1 that is essential for viral replication. Inhibition of integrase prevents HIV-1 DNA from integrating into the host genomic DNA, thereby blocking the formation of HIV-1 provirus and the spread of viral infection. Elvigravir does not inhibit human topoisomerase I or II. Elvigravir (GS-9137, JTK-303) is a potent HIV integrase strand transfer inhibitor (INSTI) with broad-spectrum activity against HIV-1 and HIV-2 [1]. Elvigravir (GS-9137, JTK-303) exerts its antiviral effect by binding to the catalytic core domain of HIV-1 integrase, inhibiting the strand transfer step of viral DNA integration into the host cell genome [1]. Elvigravir (GS-9137, JTK-303) retains partial activity against HIV-1 strains with integrase mutations associated with resistance to first-generation INSTIs [1].
Elvigravir (GS-9137, JTK-303) has shown synergistic antiviral effects with other classes of antiretroviral drugs, supporting its use in combination therapy[1]

C23H23CLFNO5

447.88

447.124

697761-98-1

Elvitegravir-d8

5277135

White to off-white solid powder

1.4±0.1 g/cm3

623.6±55.0 °C at 760 mmHg

93-96°C

330.9±31.5 °C

0.0±1.9 mmHg at 25°C

1.603

4.29

2

7

7

31

702

1

ClC1=C([H])C([H])=C([H])C(=C1F)C([H])([H])C1C(=C([H])C2=C(C=1[H])C(C(C(=O)O[H])=C([H])N2[C@]([H])(C([H])([H])O[H])C([H])(C([H])([H])[H])C([H])([H])[H])=O)OC([H])([H])[H]

JUZYLCPPVHEVSV-LJQANCHMSA-N

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

InChI=1S/C19H17N5O2.2CH4O3S/c20-17(21)14-2-1-13-10-16(8-5-12(13)9-1(4)26-18(25)11-3-6-15(7-4-11)24-19(22)23;2*1-5(2,3)4/h1-10H,(H3,20,21)(H4,22,23,24);2*1H3,(H,2,3,4

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 2.5 mg/mL (5.58 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.64 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.64 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)