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Drug Class: Integrase Inhibitors
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Drug Description |
| GS 9137 is a low-molecular-weight, highly selective integrase inhibitor that shares the core structure of quinolone antibiotics.[1] Integrase inhibitors are a new class of antiretrovirals that interfere with HIV replication by blocking viral ability to integrate into human cell genetic material.[2] |
HIV/AIDS-Related Uses |
| GS 9137 has shown in vitro activity against B and non-B subtypes of HIV-1. It is being studied in Phase II trials for the treatment of HIV-1 infection in treatment-naive and -experienced patients.[3][4] |
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Dosing Information |
Mode of Delivery |
| Oral.[5] |
Dosage Form |
| GS 9137 has been studied alone and in combination with low-dose ritonavir at doses of 200, 400, and 800 mg twice daily (BID) and 50 and 800 mg once daily (QD).[6] Phase II studies in treatment-experienced patients are evaluating once-daily doses of 25, 50, and 125 mg in combination with ritonavir 100 mg.[7] |
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Pharmacology |
GS 9137 is a modified quinolone antibiotic with potent activity against HIV-1 on in vitro assays. GS 9137 has the ability to bind magnesium cations. Integrase has a single binding site for magnesium, an ion required for strand transfer reactions and the assembly of integrase onto specific viral donor DNA. GS 9137 may be a selective inhibitor of the strand transfer process.[8][9] GS 9137 retains antiretroviral activity against multiple-drug--resistant HIV-1 in vitro.[10]
A Phase I pharmacokinetics study using single oral doses of GS 9137 was conducted in 32 healthy volunteers. Six patients in each group received daily GS 9137 doses of 100, 200, 400, or 800 mg with food or 400 mg fasting. When administered with food, GS 9137 had a half-life of approximately 3 hours, compared with a fasting half-life of approximately 6 hours. The mean maximum plasma concentration (Cmax) achieved with food was 903 ng/ml; the mean area under the concentration-time curve (AUC) with food was 3,942 ng(h)/ml. The mean Cmax in a fasted state was 264 ng/ml, and the mean fasting AUC was 1,451 ng(h)/ml. Cmax was achieved by 0.5 to 4 hours post-dose. Both Cmax and AUC increased across escalating daily doses of 100 to 800 mg in a less than dose-proportional manner.[11]
GS 9137 is mostly metabolized by the cytochrome P (CYP) 450 enzyme system, particularly CYP3A4. Glucuronidation is a minor metabolic pathway. Steady-state exposure and minimum plasma concentrations of GS 9137 increase 20-fold and 90-fold, respectively, with ritonavir boosting. Boosting also prolongs the half-life of GS 9137 to a maximum of 9.5 hours and a median of 7.6 hours. This allows for once-daily dosing of GS 9137.[12][13]
The minimum plasma concentration (Cmin) of GS 9137, rather than Cmax and AUC, appears more reflective of efficacy in pharmacokinetic models. This view is supported by a lower-than-expected antiviral effect with daily GS 9137 dosages of 800 mg; therefore, maintenance of effective trough concentrations is required for antiviral activity. Trough concentrations with once-daily, ritonavir-boosted GS 9137 doses of 50 mg provide estimated Cmins above the 95% inhibitory concentration for more than 48 hours post-dose.[14]
A randomized, double-blind, placebo-controlled trial in 40 HIV-1 infected patients not currently receiving antiretroviral therapy evaluated the effects of GS 9137 with food for 10 days. The following dosages were studied: 200, 400, and 800 mg BID; 800 mg QD; and 50 mg QD plus ritonavir 100 mg QD. In each dosage group, six patients received GS 9137, and two patients received placebo. All groups completed the 10-day dosing period and the 21 total days of evaluation, and all groups demonstrated significant antiviral activity compared with placebo. Twice-daily GS 9137 dosages of 400 or 800 mg and once-daily GS 9137 dosages of 50 mg plus ritonavir exhibited potent antiviral activity, with mean viral load reductions of at least 80-fold in each group. All patients achieved at least 50-fold viral load reduction, and half of the patients achieved at least 100-fold reduction. Maximum reductions were observed on days 10 or 11 in all but one patient. Once-daily GS 9137 dosages of 800 mg achieved a less than 10-fold viral load reduction, which was a statistically significant activity difference compared with these dosages groups.[15][16]
An ongoing, Phase II, randomized, dose-ranging monotherapy study of once-daily GS 9137 assessed noninferiority of GS 9137 to boosted comparator protease inhibitors (PIs) in HIV-infected participants. GS 9137 dosages of 20, 50, or 125 mg with ritonavir 100 mg, or comparator PIs, were administered in combination with enfuvirtide and nucleoside reverse transcriptase inhibitors (NRTIs). The 20-mg arm was closed after Week 8 because of high rate of virologic failure, and patients were offered 125 mg doses of GS 9137. The addition of PIs darunavir or tipranavir was permitted when new data showed a lack of drug interaction. Fifteen percent of patients in the 50-mg and 125-mg arms added these PIs before Week 24; by Week 24, 26% of patients in the 50-mg and 125-mg arms had added a PI in addition to their two-NRTI regimens. At Week 16, 38% of the 50-mg arm and 40% of the 125-mg arm had viral load levels less than 50 copies/ml, compared with 30% in the control arm. After Week 16, there was a significant change (p = 0.01) in viral load between the 125-mg arm and the control group: viral load decreased by -1.2log in the control arm and by -1.7log in the 125-mg arm. However, the viral load decrease of -1.4log in the 50-mg arm was not significant compared with the control. At Week 24, viral load levels less than 50 copies/ml were reported in 32% and 36% of the 50-mg and 125-mg arms, respectively, but only in 27% of the control arm.[17][18][19]
Several resistance-conferring mutations, including E92Q, H51Y, S147G, and E157Q, have been observed during serial passage studies of GS 9137. The E29Q mutation occurred after 30 passages; the other mutations occurred after at least 60 passages. In addition, cross resistance was observed between GS 9137 and prior investigational integrase inhibitors.[20] A similar study compared GS 9137 susceptibility with zidovudine and the prior investigational integrase inhibitor L-870,810. Susceptibility of HIV-1 to GS-9137 and to L-870,810 decreased dramatically in the presence of two or three identified mutations. The E29Q mutation alone conferred resistance to GS-9137 and cross resistance to L-870,810. HIV susceptibility to GS 9137 was reduced 36-fold with the E29Q mutation alone.[21][22] Additional resistance mutations identified by in vitro culturing included T66I in the integrase catalytic core, R263K in the C-terminal DNA binding domain, S153Y, and F121Y. HIV susceptibility was reduced 15-fold with the T66I mutation and 98-fold with the combined T66I/R263K mutation. In an in vitro resistance profile, mutant viruses that encoded the E92Q IN mutation has 36-fold reduced susceptibility to GS 9137 and sevenfold reduced susceptibility to raltegravir, another integrase inhibitor, but they were susceptible to all other antiretroviral classes.[23] |
Adverse Events/Toxicity |
In a single-blind, randomized, placebo-controlled trial, GS 9137 was safe and well tolerated in healthy participants; no Grade 3 or 4 adverse events occurred. One participant experienced mild anorexia, and one experienced increased liver enzyme levels; both problems resolved on their own.[24] A randomized, double-blind, placebo-controlled trial in HIV-infected participants also reported only mild adverse effects, with no Grade 3 or 4 events.[25] In a drug-interaction study of ritonavir-boosted GS 9137 and zidovudine, 2 of 24 participants experienced headache and/or gastrointestinal symptoms, both of which occurred during the zidovudine-only dosing period.[26] No serious adverse events or discontinuations resulting from adverse events occurred in this or other drug-interaction studies of GS 9137.[27]
In a 10-day monotherapy study of six participants treated with daily ritonavir-boosted GS 9137, no relationship to dose was observed in treatment-emergent Grade 3 or 4 adverse events or laboratory abnormalities. Fewer patients in the GS 9137 treatment arms than comparator arms discontinued the study drug because of adverse events.[28]
A randomized, double-blind, placebo-controlled trial of GS 9137 in 40 HIV-infected participants reported no dosage interruptions, discontinuations, or serious adverse events. Eight participants (27%) receiving GS 9137 and four (40%) receiving placebo experienced Grade 2 or 3 adverse events. Headache was the most common adverse event (occurring in three participants) and was the only adverse event to occur in more than one participant receiving GS 9137. Muscle spasm, the only Grade 3 adverse event in the treatment group, was experienced by one participant receiving 800mg of GS 9137 twice daily. Three participants receiving placebo and two receiving GS 9137 experienced a Grade 3 or 4 laboratory abnormality: one participant receiving twice-daily GS 9137 400 mg experienced Grade 3 elevated non-fasting triglycerides, and one receiving 50mg of ritonavir-boosted GS 9137 daily experienced Grade 3 elevated total amylase without increase in serum lipase.[29] |
Drug And Food Interactions |
The absorption of GS 9137 increased approximately threefold when administered with food in a Phase I study.[30]
GS 9137 displays additive to highly synergistic antiviral activity in vitro with the following antiretroviral medications: lamivudine, lamivudine/zidovudine, zidovudine, tenofovir disoproxil fumarate (tenofovir DF), tenofovir DF/lamivudine, efavirenz, indinavir, and nelfinavir.[31]
Potential drug interactions have been studied between ritonavir-boosted GS 9137 (GS 9137/r) and zidovudine or emtricitabine/tenofovir DF for up to 10 days in healthy adults and between GS 9137/r and single doses of didanosine, stavudine, or abacavir. No clinically relevant interactions were observed during GS 9137/r administration with these antiretroviral agents, and they may be coadministered without dose adjustments.[32][33][34] |
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Clinical Trials |
| Click here to search ClinicalTrials.gov for trials that use GS 9137 %20OR%20elvitegravir. |
Chemistry |
CAS Name |
| 6-(3-chloro-2-fluorobenzyl)-1- [(2S)-1hydroxy-3-methylbutan-2-yl] -7-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid[35] |
CAS Number |
| 697761-98-1[36] |
Molecular Formula |
| C23-H23-Cl-F-N-O5[37] |
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Molecular Weight |
| 447.88[38] |
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Other Names |
elvitegravir[39]
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Further Reading |
PMID/16936557 DeJesus E, Berger D, Markowitz M, Cohen C, Hawkins T, Ruane P, Elion R, Farthing C, Zhong L, Cheng AK, McColl D, Kearney BP; for the 183-0101 Study Team. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr. 2006 Sep;43(1):1-5.
PMID/16839248 Lataillade M, Kozal MJ. The hunt for HIV-1 integrase inhibitors. AIDS Patient Care STDS. 2006 Jul;20(7):489-501.
PMID/17693892 Ramanathan S, Shen G, Hinkle J, Enejosa J, Kearney BP. Pharmacokinetics of coadministered ritonavir-boosted elvitegravir and zidovudine, didanosine, stavudine, or abacavir. J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):160-6.
PMID/16509568 Sato M, Motomura T, Aramaki H, Matsuda T, Yamashita M, Ito Y, Kawakami H, Matsuaki Y, Watanabe W, Yamataka K, Ikeda S, Kodama E, Matsuoka M, Shinkai H. Novel HIV-1 Integrase Inhibitors Derived from Quinolone Antibiotics. J Med Chem 2006 Mar 9;49(5):1506-8.
PMID/17977962 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. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137).
Ritonavir-Boosted GS-9137 Vs. Ritonavir-Boosted Protease Inhibitor(s) in Combination With Background ART. Available at: http://clinicaltrials.gov/ct/show/NCT00298350. Accessed 06/24/08.
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Manufacturer Information |
GS 9137 (elvitegravir)
Gilead Sciences Inc
333 Lakeside Dr
Foster City, CA 94404
(800) 445-3235
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References |
[1] J Med Chem - 2006 Mar;49(5):1506-8
[2] Gilead Sciences - Release Archive: Gilead Announces Results from Phase I/II Study of Investigational HIV Integrase Inhibitor GS 9137 [press release], February 9, 2006. Available at: http://www.gilead.com/wt/sec/pr_815084. Accessed 06/24/08.
[3] Conf Retroviruses Opportunistic Infect - 13th, 2006. Poster 508.
[4] Conf Retroviruses Opportunistic Infect - 13th, 2006. Poster 160LB.
[5] Gilead Sciences - Press Release Archive: Gilead Announces Results from Phase I/II Study of Investigational HIV Integrase Inhibitor GS 9137 [press release], February 9, 2006. Available at: http://www.gilead.com/wt/sec/pr_815084. Accessed 06/24/08.
[6] Gilead Sciences - Press Release Archive: Gilead Announces Results from Phase I/II Study of Investigational HIV Integrase Inhibitor GS 9137 [press release], February 9, 2006. Available at: http://www.gilead.com/wt/sec/pr_815084. Accessed 06/24/08.
[7] Conf Retroviruses Opportunistic Infect - 13th, 2006. Abstract 160LB.
[8] J Med Chem - 2006 Mar;49(5):1506-8
[9] Recent Patents on Anti-Infective Drug Disc - 2006;1:1-15
[10] Conf Retroviruses Opportunistic Infect - 13th, 2006. Poster 508.
[11] Conf Retroviruses Opportunistic Infect - 13th, 2006. Poster 580.
[12] Natap.org - International Workshop on Clinical Pharmacology of HIV Therapy Summary, April 2006. Available at: http://www.natap.org/2006/7InterPharm/7InterPharm_01.htm. Abstract 75. Accessed 06/24/08.
[13] Int Conf AIDS - 16th, 2006. Abstract TUPE0088.
[14] J Acquir Immune Defic Syndr - 2006;43(1):1-5
[15] Conf Retroviruses Opportunistic Infect - 13th, 2006. Abstract 160LB.
[16] J Acquir Immune Defic Syndr - 2006;43(1):1-5
[17] Conf Retroviruses Opportunistic Infect - 14th, 2007. Abstract 143.
[18] HIV and Hepatitis.com - Conference Reports: CROI 2007. Available at: http://www.hivandhepatitis.com/2007icr/croi/docs/030607_a.html. 06/20/08. Accessed 06/24/08.
[19] Gilead Sciences - Gilead Sciences - Press Release Archive: Gilead Announces 24-Week Results from Phase II Study of Investigational HIV Integrase Inhibitor GS 9137 [press release], 03/01/07. Available at: http://www.gilead.com/pr_969229. Accessed 06/24/08.
[20] Intersci Conf Antimicrob Agents Chemother - 46th, 2006. Abstract H-254.
[21] Intersci Conf Antimicrob Agents Chemother - 46th, 2006. Abstract 161.
[22] Conf Retroviruses Opportunistic Infect - 14th, 2007. Abstract 627.
[23] Conf Retroviruses Opportunistic Infect - 14th, 2007. Abstract 627.
[24] Conf Retroviruses Opportunistic Infect - 13th, 2006. Poster 580.
[25] Conf Retroviruses Opportunistic Infect - 13th, 2006. Abstract 160LB.
[26] Int Conf AIDS - 16th, 2006. Abstract TUPE0088.
[27] Conf Retroviruses Opportunistic Infect - 16th, 2006. Abstract TUPE0080.
[28] Conf Retroviruses Opportunistic Infect - 14th, 2007. Abstract 143LB.
[29] J Acquir Immune Defic Syndr - 2006;43(1):1-5
[30] Conf Retroviruses Opportunistic Infect - 13th, 2006. Poster 580.
[31] Conf Retroviruses Opportunistic Infect - 13th, 2006. Poster 508.
[32] Int Conf AIDS - 16th, 2006. Abstract TUPE0088.
[33] Int Conf AIDS - 16th, 2006. Abstract TUPE0080.
[34] J Acquir Immune Defic Syndr - 2007 Oct 1;46(2):160-6.
[35] Conf Retroviruses Opportunistic Infect - 13th, 2006. Poster 508.
[36] ChemIDplus - http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 06/24/08.
[37] ChemIDplus - http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 06/24/08.
[38] Conf Retroviruses Opportunistic Infect - 13th, 2006. Poster 508.
[39] Gilead Sciences - March 2007 Press Release: Gilead Announces 24-Week Results from Phase II Study of Investigational HIV Integrase Inhibitor GS 9137. Available at: http://www.gilead.com/pr_969229. Accessed 06/24/08.
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Updated June 24, 2008
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