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Elvitegravir

Brand Name: Vitekta Other Names: EVG Drug Class: Integrase Inhibitors

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elvitegravir

elvitegravir

Molecular Weight: 447.8877

Drug Description


Elvitegravir (EVG), also known as 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]


References

[1] J Med Chem 2006 Mar;49(5):1506-8

[2] 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 08/30/11.

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 and Phase III trials for the treatment of HIV-1 infection in treatment-naïve and -experienced patients. [1] [2] [3]


References

[1] Conf Retroviruses Opportunistic Infect 13th, 2006. Poster 508.

[2] Conf Retroviruses Opportunistic Infect 13th, 2006. Poster 160LB.

[3] ClinicalTrials.gov – Elvitegravir List Results. Available at: http://www.clinicaltrials.gov/ct2/results?term=elvitegravir. Accessed 08/30/11.

Dosing Information


Mode of Delivery

Oral. [1]

Dosage Form

EVG has been studied alone and in combination with low-dose ritonavir (RTV) at doses of 200, 400, and 800 mg twice daily (BID) and 50 and 800 mg once daily (QD). [2] Phase II studies in treatment-experienced patients have evaluated EVG dosed daily at 20, 50, and 125 mg in combination with ritonavir 100 mg. [3]

A Phase III trial of RTV-boosted EVG 150 mg (tablet) once-daily administered with a background regimen is ongoing.  For subjects randomized to the experimental treatment arm taking RTV-boosted atazanavir (ATV) or RTV-boosted lopinavir (LPV) as part of their background regimen, RTV-boosted EVG 85 mg (tablet) once-daily will be administered.[4]

Elvitegravir is also being evaluated in Phase III trials as part of a once-daily single-tablet “Quad” regimen containing EVG 150 mg, cobicistat 150 mg, emtricitabine (FTC) 200 mg and tenofovir disoproxil fumarate (TDF) 300 mg. [5] 


References

[1] 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 08/30/11.

[2] 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 08/30/11.

[3] J Infect Dis. 2010 Mar 15;201(6):814-22.

[4] ClinicalTrials.gov—Multicenter, Randomized, Double-Blind, Double-Dummy, Phase 3 Study of the Safety and Efficacy of Ritonavir-Boosted Elvitegravir (EVG/r) Versus Raltegravir (RAL). Available at: http://www.clinicaltrials.gov/ct2/show/NCT00708162. Accessed 08/30/11.

[5] Gilead Sciences Press Release Archive: Gilead Initiates Phase III Clinical Program Evaluating Single-Tablet, Once-Daily “Quad” Regimen for HIV [press release], April 12, 2010. Available at: http://www.gilead.com/pr_1411934. Accessed 08/30/11.

Pharmacology


GS 9137 is a modified quinolone antibiotic with potent activity against HIV-1 in vitro. 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. [1] [2] GS 9137 retains antiretroviral activity against multiple drug--resistant HIV-1 in vitro. [3]

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 without food or 400 mg with food. When administered with food, GS 9137 had a half-life of approximately 3.2 hours, compared with a fasting half-life of approximately 5.4 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.  Mean time to maximum plasma concentration (tmax) in the fasted and fed states were 2.5 hr and 2.3 hr, respectively. Both Cmax and AUC increased across escalating daily doses of 100 to 800 mg in a less than dose-proportional manner. [4]

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. [5]

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 are estimated to remain above the 95% inhibitory concentration (IC95) for more than 48 hours post-dose. [6]

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 dosage groups. [7] [8]

Study GS-236-0101, a Phase I open-label, partially-randomized study evaluated two versions of a fixed-dose single tablet regimen containing either cobicistat (COBI) 100 mg or cobicistat 150  mg, each with EVG, FTC, and TDF versus RTV 100 mg-boosted EVG, FTC/TDF. Data indicate that the 150 mg cobicistat dose resulted in maintenance of targeted high EVG trough concentrations (Ctau) based on RTV-boosting.  Additionally, the fixed-dose combination tablet containing cobicistat 150 mg resulted in clinically equivalent tenofovir and FTC exposures compared to FTC/TDF administered individually. [9]

Study 183-0105 is a Phase II, randomized, dose-ranging trial of once-daily GS 9137 assessing noninferiority of GS 9137 to boosted comparator protease inhibitors (PIs) in HIV-infected participants. Patients were randomized to receive either once-daily GS 9137 20 mg (n=71), 50 mg (n=71), or 125 mg (n=73), each with RTV 100 mg, or boosted comparator PIs (CPI/r) (n=63), all in combination with an optimized background regimen of two or more nucleoside reverse transcriptase inhibitors (NRTIs) with or without enfuvirtide (T-20). Patients receiving T-20 were stratified across treatment arms. The GS 9137 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 interactions between both PIs and GS 9137. The primary endpoint of the study was time-weighted average change from baseline in HIV RNA loads through 24 weeks (DAVG24). The mean DAVG24 for patients in the GS 9137 50 mg arm was -1.4 log copies/mL versus -1.2 log copies/mL for the comparator arm (p=0.27). For patients receiving GS 9137 125 mg versus the comparator arm, the mean DAVG24 was -1.7 log copies/mL and -1.2 log copies/mL, respectively; (p=0.02). In the GS 9137 125 mg group, patients receiving T-20 for the first time, or those who had one or more active NRTIs in their background therapy, experienced significantly greater mean reductions in viral load at 24 weeks compared to those with no active NRTIs and no first use of T-20 (-2.1 log copies/mL versus -0.7 log copies/mL, respectively; p <0.001).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. 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, compared with 27% of the control arm. [10] [11] [12] [13]

Study 236-0104 is a double-blind, randomized, active-controlled, 48-week Phase II trial evaluating the safety and efficacy of a fixed-dose single-tablet “Quad” regimen (EVG 150 mg/cobicistat 150 mg/FTC 200 mg/TDF 300 mg) (n=48) versus efavirenz 600 mg/FTC 200 mg/TDF 300 mg (Atripla) (n=23) among HIV-infected treatment-naïve adults.  The primary efficacy endpoint, the proportion of subjects with HIV-1 RNA less than 50 copies/mL at Week 24, was achieved by 90% of patients in the “Quad” arm and 83% of patients in the Atripla arm. Patients in the “Quad” group experienced a median increase in CD4 cell count of 123 cells/mm3 compared to a median increase of 124 cells/mm3 among Atripla patients at 24 weeks. Study investigators have reported that this study has low power for formal efficacy comparisons; however, efficacy of the “Quad” met statistical criteria of non-inferiority as compared to Atripla as defined by a pre-specified lower bound of the non-inferiority margin of -12%. At Week 48, 90% patients in the “Quad” arm and 83% of patients in the Atripla arm achieved HIV-1 RNA levels of less than 50 copies/mL. Patients taking the “Quad” versus Atripla patients experienced a mean increase in CD4 cell counts of 240 cells/mm3 compared to 162 cells/mm3, respectively, at 48 weeks. [14] [15] [16]

Study 236-0102 is a Phase III, randomized, double-blind trial evaluating the safety and efficacy of the “Quad” regimen (EVG 150 mg/cobicistat 150 mg/FTC 200 mg/TDF 300 mg) versus Atripla in HIV-1 infected, antiretroviral treatment-naïve adults. The study met its primary objective, non-inferiority at week 48 as compared to Atripla. The primary efficacy endpoint, the proportion of subjects achieving and maintaining HIV-1 RNA less than 50 copies/mL through Week 48, was achieved by 88% of patients in the “Quad” group and 84% of patients in the Atripla arm (95% CI for the difference: -1.6% to 8.8%). The mean 48-week increase in CD4 cell count from baseline was 239 cells/mm3 and 206 cells/mm3, in the “Quad” arm and the Atripla arm, respectively (p=0.009). This study is ongoing in a blinded fashion. [17] [18]

A second pivitol “Quad” trial, Study 236-0103, a randomized, double-blind trial comparing the safety and efficacy of the “Quad” regimen versus RTV-boosted atazanavir and FTC 200 mg/TDF 300 mg (Truvada), is ongoing. [19] [20]

Study 145 is a Phase III, randomized, double-blind, 48-week clinical trial evaluating the non-inferiority of once-daily EVG 150 mg (n=351) versus twice-daily raltegravir (RAL) 400 mg (n=351), each administered with a background regimen in HIV-infected treatment-experienced adults with HIV RNA (viral load) of greater than or equal to 1,000 copies/mL. Patients have documented viral resistance, as defined by International AIDS Society-USA guidelines, or at least six months of treatment with two or more different classes of antiretroviral agents prior to screening. Background regimens are based on the results of resistance testing and include a fully-active RTV-boosted PI, and a second agent that may be a NRTI, etravirine, maraviroc or enfuvirtide. Because of known interactions, EVG patients whose background PI is either atazanavir or lopinavir receive an 85 mg dose of elvitegravir. The primary endpoint of this study was non-inferiority at Week 48 of EVG, dosed once daily, compared to RAL, dosed twice daily. Week 48 primary endpoint analysis indicated that 59.0 percent of patients in the EVG arm compared to 57.8 percent in the RAL arm (95% CI for the difference: -6.0% to +8.2%) achieved and maintained a viral load of less than 50 copies/mL. The predefined criterion for non-inferiority was a lower bound of a two sided 95% CI of -10 percent. Reported mean increase in CD4 cell counts was 138 cells/mm3 and 147 cells/mm3 in the EVG arm and the RAL arm, respectively. Twenty-six percent (16/62) of EVG patients developed integrase resistance compared to 20% (15/76) of patients in the RAL group. The blinded, randomized period of the study has been extended to up to 96 weeks. [21] [22]

Several resistance-conferring mutations, including E92Q, H51Y, S147G, and E157Q, have been observed during serial passage studies of GS 9137. The E92Q 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. [23] 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 E92Q 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 E92Q mutation alone. [24] [25] [26] 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. [27] [28]

A study using generated recombinant integrase proteins and viruses harboring raltegravir resistance mutations indicates that RAL resistance pathways involving mutations at integrase position 148 and 155 confer cross-resistance to EVG; however, EVG remains fully active against the Y143R mutant integrase and virus particles. [29]


References

[1] J Med Chem 2006 Mar;49(5):1506-8

[2] Recent Patents on Anti-Infective Drug Disc 2006;1:1-15

[3] Conf Retroviruses Opportunistic Infect 13th, 2006. Poster 508.

[4] Conf Retroviruses Opportunistic Infect 13th, 2006. Poster 580.

[5] 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 08/30/11.

[6] J Acquir Immune Defic Syndr 2006;43(1):1-5

[7] J Acquir Immune Defic Syndr 2006;43(1):1-5

[8] Conf Retroviruses Opportunistic Infect 13th, 2006. Abstract 160LB.

[9] Gilead Sciences Press Release Archive: Gilead Announces Data Demonstrating Pharmacokinetic Boosting Activity of GS 9350 [press release], February 9, 2009. Available at: http://www.gilead.com/pr_1254580. Accessed 08/30/11.

[10] Conf Retroviruses Opportunistic Infect 14th, 2007. Abstract 143.

[11] Natap.org The HIV Integrase Inhibitor GS-9137 Has Potent Antiretroviral Activity in Treatment-Experienced Patients. Conference Reports, February 2007. Available at: http://www.natap.org/2007/CROI/croi_20.htm. Accessed 08/30/11.

[12] Gilead Sciences - Press Release Archive: Gilead Announces 24-Week Results from Phase II Study of Investigational HIV Integrase Inhibitor GS 9137 [press release], March 1, 2007. Available at: http://www.gilead.com/pr_969229. Accessed 08/30/11.

[13] ClinicalTrials.gov—Ritonavir-Boosted GS-9137 vs. Ritonavir-Boosted Protease Inhibitor(s) in Combination With Background ART. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00298350. Accessed 08/30/11.

[14] Gilead Sciences Press Release Archive: Gilead’s Single-Tablet “Quad” Regimen for HIV Achieves a High Rate of Virologic Suppression in Phase II Study [press release], February 17, 2010. Available at: http://www.gilead.com/pr_1391910. Accessed 08/30/11.

[15] ClinicalTrials.gov—Study of the Safety and Efficacy of Elvitegravir/Emtricitabine/Tenofovir Disoproxil Fumarate/GS-9350 (QUAD) Versus Atripla in HIV Infected, Antiretroviral Treatment-Naïve Adults. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00869557. Accessed 08/30/11.

[16] Gilead Sciences Press Release Archive: Gilead’s Single-Tablet “Quad” HIV Regimen Maintains High Viral Suppression Through 48 Weeks in Phase II Study [press release], September 13, 2010. Available at: http://www.gilead.com/pr_1470367. Accessed 08/30/11.

[17] Gilead Sciences Press Release Archive: Gilead's Investigational Antiretroviral Quad Regimen Meets 48-Week Primary Objective in Pivotal Phase 3 Clinical Study 102 [press release], August 15, 2011. Available at: http://www.gilead.com/pr_1596378. Accessed 08/30/11.

[18] ClinicalTrials.gov— Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Elvitegravir/Emtricitabine/Tenofovir Disoproxil Fumarate/GS-9350 Versus Efavirenz/Emtricitabine/ Tenofovir Disoproxil Fumarate in HIV-1 Infected, Antiretroviral Treatment-Naïve Adults. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01095796. Accessed 08/30/11.

[19] Gilead Sciences Press Release Archive: Gilead's Investigational Antiretroviral Quad Regimen Meets 48-Week Primary Objective in Pivotal Phase 3 Clinical Study 102 [press release], August 15, 2011. Available at: http://www.gilead.com/pr_1596378. Accessed 08/30/11.

[20] ClinicalTrials.gov— Study to Evaluate the Safety and Efficacy of Elvitegravir/Emtricitabine/Tenofovir Disoproxil Fumarate/GS-9350 Versus Ritonavir-Boosted Atazanavir Plus Emtricitabine/Tenofovir Disoproxil Fumarate in HIV-1 Infected, Antiretroviral Treatment-Naïve Adults. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01106586. Accessed 08/30/11.

[21] Gilead Sciences Press Release Archive: Phase III Clinical Trial of Gilead's Investigational Elvitegravir Meets 48-Week Primary Objective [press release], March 23, 2011. Available at: http://www.gilead.com/pr_1542005. Accessed 08/30/11.

[22] 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention, 2011. Abstract WELBB05. Available at: http://pag.ias2011.org/abstracts.aspx?aid=4757. Accessed 08/30/11.

[23] Intersci Conf Antimicrob Agents Chemother 46th, 2006. Abstract H-254.

[24] Intersci Conf Antimicrob Agents Chemother 46th, 2006. Abstract 161.

[25] Conf Retroviruses Opportunistic Infect 14th, 2007. Abstract 627.

[26] Natap.org Cell Studies Predict Cross-Resistance Among Integrase Inhibitors, September 2006. Available at: http://www.natap.org/2006/ICAAC/ICAAC_48.htm. Accessed 08/30/11.

[27] Conf Retroviruses Opportunistic Infect 14th, 2007. Abstract 627.

[28] Natap.org In Vitro Resistance Profile of HIV-1 Mutants Selected by the HIV-1 Integrase Inhibitor, GS-9137 (JTK-303), February 2007. Available at: http://www.natap.org/2007/CROI/croi_61.htm. Accessed 08/30/11.

[29] AIDS. 2011 Jun 1;25(9):1175-8.

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. [1] A randomized, double-blind, placebo-controlled trial in HIV-infected participants also reported only mild adverse effects, with no Grade 3 or 4 events. [2] In a drug-interaction study of ritonavir-boosted GS 9137 and zidovudine, discontinuations included 2 of 24 participants who experienced headache and/or gastrointestinal symptoms, the onset occurring during the zidovudine-only dosing period. [3]

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, occurring in three participants, was the only Grade 2 adverse event that occurred in more than one subject receiving GS 9137. Muscle spasm, the only Grade 3 adverse event in the treatment group, was experienced by one participant receiving twice-daily GS 9137 800 mg. Three participants receiving placebo and two receiving GS 9137 experienced a Grade 3 or 4 laboratory abnormality. These include two reports of Grade 3 elevated total amylase without an increase in serum lipase (one each in daily GS 9137 50 mg plus ritonavir and placebo), one Grade 3 elevated nonfasting triglyceride (one in twice-daily GS 9137 400 mg), a Grade 4 creatine kinase (placebo), and one Grade 3 alanine aminotransferase (placebo).[4]

Week 48 safety data from a Phase II trial, Study 236-0104, demonstrated a similar discontinuation rate and adverse events profile in both arms (“Quad” versus Atripla). Three patients discontinued treatment in each arm of the study. The rates of adverse events were similar between treatment arms; however, fewer central nervous system (CNS) side effects were observed among “Quad” patients. The most common adverse events reported in greater than 5% of patients in either treatment arm were abnormal dreams/nightmares, dizziness, fatigue, somnolence, diarrhea, headache, anxiety, nausea, abdominal distension and rash. There were two Grade 3 or 4 adverse events in the “Quad” group (pneumonia and anogenital warts) and two among Atripla patients (B-cell lymphoma with lymphadenopathy and neutropenia). A similar incidence of laboratory abnormalities (Grades 2-4) was reported across both arms of the study. Laboratory abnormalities seen in greater than 5% of subjects in either treatment arm included increases in amylase, hypercholesterolemia, creatine kinase changes, decreased neutrophils, and proteinuria. Similar mean changes in cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides occurred in both treatment groups. [5]

Study 236-0102 48-week data showed similar safety profiles between both the “Quad” arm and the Atripla-treated arm. The frequency of Grade 3-4 adverse events, laboratory abnormalities, and discontinuation rates due to adverse events were comparable in both arms of the study. [6]

In Study 145, a phase III trial comparing EVG dosed once daily to RAL dosed twice daily, adverse events, laboratory abnormalities, and discontinuation rates due to adverse events were reported as being comparable in both arms of the study at 48 weeks. [7] [8]


References

[1] Conf Retroviruses Opportunistic Infect 13th, 2006. Poster 580.

[2] Conf Retroviruses Opportunistic Infect 13th, 2006. Abstract 160LB.

[3] Int Conf AIDS 16th, 2006. Abstract TUPE0088.

[4] J Acquir Immune Defic Syndr 2006;43(1):1-5

[5] Gilead Sciences Press Release Archive: Gilead’s Single-Tablet “Quad” HIV Regimen Maintains High Viral Suppression Through 48 Weeks in Phase II Study [press release], September 13, 2010. Available at: http://www.gilead.com/pr_1470367. Accessed 08/30/11.

[6] Gilead Sciences Press Release Archive: Gilead's Investigational Antiretroviral Quad Regimen Meets 48-Week Primary Objective in Pivotal Phase 3 Clinical Study 102 [press release], August 15, 2011. Available at: http://www.gilead.com/pr_1596378. Accessed 08/30/11.

[7] Gilead Sciences Press Release Archive: Phase III Clinical Trial of Gilead's Investigational Elvitegravir Meets 48-Week Primary Objective [press release], March 23, 2011. Available at: http://www.gilead.com/pr_1542005. Accessed 08/30/11.

[8] 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention, 2011. Abstract WELBB05. Available at: http://pag.ias2011.org/abstracts.aspx?aid=4757. Accessed 08/30/11.

Drug and Food Interactions


The absorption of GS 9137 increased approximately threefold when administered with food in a Phase I study. [1]

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. [2]

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. [3] [4] [5]

Due to drug-drug interactions, a dose reduction of elvitegravir from 150 mg to 85 mg when coadministered with atazanavir/ritonavir or lopinavir/ritonavir is necessary. [6]

When administering elvitegravir/r plus maraviroc, elvitegravir and ritonavir dose modifications are not needed; however, a reduced 150 mg dose of maraviroc is recommended. [7]


References

[1] Conf Retroviruses Opportunistic Infect 13th, 2006. Poster 580.

[2] Conf Retroviruses Opportunistic Infect 13th, 2006. Poster 508.

[3] Int Conf AIDS 16th, 2006. Abstract TUPE0088.

[4] Int Conf AIDS 16th, 2006. Abstract TUPE0080.

[5] J Acquir Immune Defic Syndr 2007 Oct 1;46(2):160-6.

[6] Clin Pharmacokinet. 2011 Apr 1;50(4):229-44.

[7] J Acquir Immune Defic Syndr. 2010 Feb 1;53(2):209-14.

Clinical Trials


Click here to search ClinicalTrials.gov for trials that use Elvitegravir.


Chemistry



Further Reading



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.
Lataillade M, Kozal MJ. The hunt for HIV-1 integrase inhibitors. AIDS Patient Care STDS. 2006 Jul;20(7):489-501.
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.
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.
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).
Zolopa AR, Berger DS, Lampiris H, Zhong L, Chuck SL, Enejosa JV, Kearney BP, Cheng AK. Activity of elvitegravir, a once-daily integrase inhibitor, against resistant HIV type 1: results of a phase 2, randomized, controlled, dose-ranging clinical trial. J Infect Dis 2010; 201:814–22.
German P, Warren D, West S, Hui J, Kearney BP. Pharmacokinetics and bioavailability of an integrase and novel pharmacoenhancer-containing single-tablet fixed-dose combination regimen for the treatment of HIV. J Acquir Immune Defic Syndr. 2010 Nov 1;55(3):323-9.
Métifiot M, Vandegraaff N, Maddali K, Naumova A, Zhang X, Rhodes D, Marchand C, Pommier Y. Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143. AIDS. 2011 Jun 1;25(9):1175-8.
Ramanathan S, Mathias AA, German P, Kearney BP. Clinical pharmacokinetic and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin Pharmacokinet. 2011 Apr 1;50(4):229-44.
Ramanathan S, Abel S, Tweedy S, West S, Hui J, Kearney BP. Pharmacokinetic interaction of ritonavir-boosted elvitegravir and maraviroc. J Acquir Immune Defic Syndr. 2010 Feb 1;53(2):209-14.


Last Reviewed: August 20, 2014

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