Abstract
Elvitegravir is a potent, boosted, once-daily, HIV integrase inhibitor with antiviral activity against wild-type and drug-resistant strains of HIV. Because elvitegravir is metabolized primarily by cytochrome P450 (CYP) 3A enzymes, coadministration with a strong CYP3A inhibitor such as ritonavir or cobicistat (also known as GS-9350), an investigational pharmacoenhancer, substantially increases (boosts) elvitegravir plasma exposures and prolongs its elimination half-life to ∼9.5 hours, allowing once-daily administration of a low 150 mg dose. Boosting also results in low intra- and intersubject pharmacokinetic variability and high elvitegravir trough concentrations (∼6- to 10-fold above the concentration producing 95% inhibition of wild-type HIV-1 virus [IC95] of 45 ng/mL [protein binding-adjusted]), which is the pharmacokinetic parameter best associated with its antiviral activity.
Data from extensive evaluation of the potential for boosted elvitegravir to undergo drug-drug interactions with other antiretroviral agents or concomitant medications indicate the absence of clinically relevant interactions or the need for dose modification in several cases, except for dose reduction of elvitegravir from 150 to 85 mg when coadministered with atazanavir/ritonavir or lopinavir/ritonavir. Dose adjustments for maraviroc and rifabutin, when each is coadministered with boosted elvitegravir, are consistent with their observed interactions with other ritonavir-boosted agents. The presence of a strong CYP3A inhibitor such as ritonavir or cobicistat renders the potential for increase in systemic exposures of CYP3A substrates coadministered with boosted elvitegravir. This article reviews a comprehensive pharmacology programme, including drug-drug interaction studies, mechanistic and special population studies, that has allowed a thorough understanding of elvitegravir clinical pharmacokinetics and its impact on pharmacodynamics.
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References
Kearney BP, Mathias A, Zhong L, et al. Pharmacokinetics/pharmacodynamics of GS-9137 an HIV integrase inhibitor [abstract no. 73 plus oral presentation]. Rev Antivir Ther 2006; 3: 80
Mathias AA, German P, Lee M, et al. GS-9350: A pharmacoenhancer without anti-HIV activity [abstract no. 40 plus oral presentation]. 16th Conference on Retroviruses and Opportunistic Infections; 2009 Feb 8–12; Montreal (QC)
Elion R, Gathe J, Rashbaum B, et al. The single tablet regimen of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (QUAD) maintains a high rate of virologic suppression, and cobicistat is an effective pharmacoenhancer through 48 weeks [abstract no. H-938b]. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 2010 Sep 12–15; Boston (MA)
Zolopa AR, Berger DS, Lampiris H, et al. 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 Mar; 201: 814–22
DeJesus E, Berger D, Markowitz M, et al. 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
Shimura K, Kodama E, Sakagami Y, 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
Shimura K, Kodama EN. Elvitegravir: a new HIV integrase inhibitor. Antivir Chem Chemother 2009 Oct; 20: 79–85
McColl DJ, Chen X. Strand transfer inhibitors of HIV-1 integrase: bringing in a new era of antiretroviral therapy. Antivir Res 2010; 85: 101–18
Ledford RM, Margot NA, Miller MD, et al. Elvitegravir (GS-9137/JTK-303), an HIV-1 integrase inhibitor, has additive to synergistic interactions with antiretroviral drugs in vitro [abstract no. MOPEA052 plus poster]. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention; 2007 Jul 22–25; Sydney (NSW)
Stanfield-Oakley SA, Davison D, Bowling TS, et al. Synergistic in vitro antiretroviral activity of enfuvirtide and elvitegravir (GS-9137) [abstract no. H-1051 plus poster]. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2007 Sep 17–20; Chicago (IL)
Matsuzaki Y, Watanabe W, Yamataka K. JTK-303/GS-9137, a novel small molecule inhibitor of HIV-1 integrase: anti-HIV activity profile and pharma-cokinetics in animals [abstract no. 508 plus poster]. 13th Conference on Retroviruses and Opportunistic Infections; 2006 Feb 5–9; Denver (CO)
Kawaguchi I, Ishikawa T, Ishibashi M, et al. Safety and pharmacokinetics of single oral dose of JTK-303/GS-9137, a novel HIV integrase inhibitor, in healthy volunteers [abstract no. 580 plus poster]. 13th Conference on Retro-viruses and Opportunistic Infections; 2006 Feb 5–9; Denver (CO)
Mathias AA, West S, Hui J, et al. Dose-response of ritonavir on hepatic CYP3A activity and elvitegravir oral exposure. Clin Pharmacol Ther 2009 Jan;85(1): 64–70
Ramanathan S, Khariton T, West S, et al. Population pharmacokinetics of ritonavir-boosted elvitegravir in adult healthy subjects and HIV-infected patients [abstract no. 40 plus poster]. Rev Antivir Ther 2008; 3: 78
Collot-Teixeira S, De Lorenzo F, Waters L, et al. Impact of different low dose ritonavir regimens on lipids, CD36, and adipophilin expression. Clin Pharmacol Ther 2009 Apr;85(4): 375–8
Shafran SD, Mashinter LD, Roberts SE. The effect of low-dose ritonavir monotherapy on fasting serum lipid concentrations. HIV Med 2005; 6(6): 421–5
Flexner C. HIV drug development: the next 25 years. Nat Rev Drug Discov 2007; 6(12): 959–66
Ramanathan S, Shen G, Hinkle J. Pharmacokinetic evaluation of drug interactions with ritonavir-boosted HIV integrase inhibitor GS-9137(elvitegravir) and acid-reducing agents [abstract no. 69 plus poster]. 8th International Workshop on Clinical Pharmacology of HIV Therapy; 2007 Apr 16–18; Budapest
Data on file, Gilead Sciences, Inc., 2006
Ramanathan S, Wright M, West S, et al. Pharmacokinetics, metabolism and excretion of ritonavir-boosted GS-9137(elvitegravir) [abstract no. 30 plus poster]. 8th International Workshop on Clinical Pharmacology of HIV Therapy; 2007 Apr 16–18; Budapest
Ramanathan S, Mathias AA, Hinkle J, et al. Clinical pharmacology of the HIV integrase inhibitor elvitegravir [abstract no. PS 4/7 plus oral presentation]. 11th European AIDS Conference; 2007 Oct 24–27; Madrid
Song I, Chen S, Lou, Y et al. Pharmacokinetic (PK) and pharmacodynamic (PD) relationship of S/GSK1349572, a next generation integrase inhibitor (INI), in HIV-1 infected patients [abstract no. WePeA098 plus poster]. 5th IAS on HIV Pathogenesis, Treatment and Prevention; 2009 Jul 19–22; Cape Town
Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 2009 Sep;374(9692): 796–806
Steigbigel RT, Cooper DA, Teppler H, et al. Long-term efficacy and safety of raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 phase III trials. Clin Infect Dis 2010 Feb 15; 50(4): 605–12
Markowitz M, Morales-Ramirez JO, Nguyen B-Y, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naïve HIV-1 infected patients. J Acquir Immune Defic Syndr 2006 Dec;43(5): 509–15
Isentress® (raltegravir) tablets: US prescribing information. Whitehouse Station (NJ): Merck Sharp & Dohme Corp., 2010 Jun [online]. Available from URL: http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf [Accessed 2011 Jan 27]
Hazuda D, Iwamoto M, Wening L. Emerging pharmacology: inhibitors of human immunodeficiency virus integration. Annu Rev Pharmacol Toxicol 2009; 49: 377–94
Hluhanich R, Kinkade A, Margot NA, et al. HIV integrase inhibitor do not exert a post-antibiotic effect despite slow dissociation from IN-DNA complexes in vitro [abstract no. H-930 plus poster]. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2009 Sep 12–15; San Francisco (CA)
German P, Warren D, and Wei L, et al. Effect of food on pharmacokinetics of elvitegravir, emtricitabine, tenofovir DF and the pharmacoenhancer GS-9350 as a fixed-dose combination tablet. [abstract no. A1-1300 plus poster]. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2009 Sep 12–15; San Francisco (CA)
Gaur A, Abadi J, Wiznia A, et al. Pharmacokinetics and safety of once-daily elvitegravir in HIV-infected adolescents [abstract no. S-109 plus poster] 17th Conference on Retrovirus and Opportunistic Infection; 2010 Feb 16–19; San Francisco (CA)
Ziagen® (abacavir sulfate) tablets and oral solution: US prescribing information. Research Triangle Park (NC): GlaxoSmithKline, 2010 Sep [online]. Available from URL: http://us.gsk.com/products/assets/us_ziagen.pdf [Accessed 2011 Jan 27]
Water LJ, Moyle G, Bonora S, et al. Abacavir plasma pharmacokinetics in the absence and presence of atazanavir/ritonavir or lopinavir/ritonavir and vice versa in HIV-infected patients. Antivir Ther 2007; 12: 825–30
Sahai J, Gallicano K, Oliveras L, et al. Cations in the didanosine tablet reduce ciprofloxacin bioavailability. Clin Pharmacol Ther 1993; 53: 292–7
Cato A, Qian J, Hsu A. Pharmacokinetic interaction between ritonavir and didanosine when administered concurrently to HIV infected patients. J Acquir Immune Defic Syndr Human Retrovir 1998 Aug;18(5): 466–72
Viread® (tenofovir disoproxil fumarate) tablets: US prescribing information. Foster City (CA): Gilead Sciences, Inc., 2010 Oct [online]. Available from URL: http://www.viread.com/common/Viread_FPI.pdf [Accessed 2011 Jan 27]
Ramanathan S, Shen G, Cheng A, et al. Pharmacokinetics of emtricitabine, tenofovir, and GS-9137 following coadministration of emtricitabine/ tenofovir disoproxil fumarate and ritonavir-boosted GS-9137. J Acquir Immune Defic Syndr 2007 Jul;45(3): 274–9
Ramanathan S, Shen G, Hinkle J, et al. Pharmacokinetics of coadministered ritonavir-boosted elvitegravir and zidovudine, didanosine, stavudine, or abacavir. J Acquir Immune Defic Syndr 2007 Oct;46(2): 160–6
Mathias A, Hinkle J, Shen G, et al. Effect of ritonavir-boosted tipranavir or darunavir on the steady-state pharmacokinetics of elvitegravir. J Acquir Immune Defic Syndr 2008 Oct;49(2): 156–62
Sekar V, De Paepe E, Van Baelen B, et al. Pharmacokinetic/pharmacodynamic (PK/PD) analyses of darunavir in the TITAN study [abstract no. P 4.1/10 plus poster]. 11th European AIDS Conference; 2007 Oct 24–27; Madrid
Sekar V, De Meyer S, Vangeneugden T, et al. Absence of TMC114 exposure-efficacy and exposure-safety relatiohsips in POWER 3 [abstract no. TUPE 0078 plus poster]. 16th International AIDS Conference; 2006 Aug 13–18; Toronto (ON)
Boffito M, Maitland D, Pozniak A. Practical perspectives on the use of tipranavir in combinations with other medications: lessons learned from pharmacokinetic studies. J Clin Pharmacol 2006 Feb;46(2): 130–9
Vourvahis M, Dumond J, Patterson K, et al. Effects of tipranavir/ritonavir (TPV/r) on the activity of hepatic and intestinal cytochrome P450 3A4/5 and P-glycoprotein (P-gp): implications for drug interactions [abstract no. 563 plus poster]. 14th Conference on Retrovirus and Opportunistic Infections; 2007 Feb 25–28; Los Angeles (CA)
Tran JQ, Petersen C, Garrett M, et al. Pharmacokinetic interaction between amprenavir and delavirdine: evidence of induced clearance by amprenavir. Clin Pharmacol Ther 2002 Dec;72(6): 615–26
Wire MB, Shelton MJ, Lou Y, et al. The pharmacokinetic interaction between fosamprenavir/ritnonavir and atazanavir in healthy adult subjects (APV 10018) [abstract no, PE 4.3/9 plus poster]. 10th European AIDS Conference; 2005 Nov 17–20; Dublin
Boffito M, Dickinson L, Hill A, et al. Steady-state pharmacokinetics of saquinavir hard-gel/ritonavir/fosamprenavir in HIV-1 infected patients. J Acquir Immune Defic Syndr 2004; 37: 1376–84
Kashuba A, Tierney C, Downey GF. Combining fosamprenavir with lopinavir/ritonavir substantially reduces amprenavir and lopinavir exposure: ACTG protocol A5143 results. AIDS 2005; 19: 145–52
Wire MB, Naderer OJ, Masterman AL, et al. The pharmacokinetic (PK) interaction between GW433908(908) with lopinavir (LPV)/ritonavir (RTV)(APV 10011 and APV 10012) [abstract no. 612 plus poster]. 11th Conference of Retrovirus and Opportunistic Infections; 2004 Feb 8–11; San Francisco (CA)
Corbett AH, Patterson KB, Tien H-C, et al. Dose separation does not overcome the pharmacokinetic interaction between fosamprenavir and lopinavir/ ritonavir. Antimicrob Agents Chemother 2006 Aug;50(8): 2756–61
Ramanathan S, Mathias A, Shen G, et al. Lack of clinically relevant drug-drug interaction between ritonavir-boosted GS-9137(elvitegravir) and fosamprenavir/r [abstract no. WEPEB014 plus poster]. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention; 2007 Jul 22–25; Sydney (NSW)
Mathias A, Ramanathan S, Hinkle J, et al. Effect of atazanavir/r on the steady-state pharmacokinetics of elvitegravir [abstract no. A1417 plus poster]. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2007 Sep 17–20; Chicago (IL)
Mathias A, Ramanathan S, Hinkle J, et al. A pharmacokinetic interaction between lopinavir/r and elvitegravir [abstract no. A1418 plus poster]. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2007 Sep 17–20; Chicago (IL)
Zhang D, Chando TJ, Everett DW, et al. In vitro inhibition of UDP glucur-onosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos 2005 Nov;33(11): 1729–39
Schöller-Gyüre M, Kakuda TN, Raoof A, et al. Clinical pharmacokinetics and pharmacodynamics of etravirine. Clin Pharmacokinet 2009; 48(9): 561–74
Ramanathan S, Kakuda T, Mack R, et al. Pharmacokinetics of elvitegravir and etravirine following coadministration of ritonavir-boosted elvitegravir and etravirine. Antivir Ther 2008; 13: 1011–7
Hyland R, Dickins M, Collins C, et al. Maraviroc: in vitro assessment of drug-drug interaction potential. Br J Clin Pharmacol 2008 Oct; 66: 498–507
Walker DK, Abel S, Comby P, et al. Species differences in the disposition of the new CCR5 antagonist, UK-427,857, a new potential treatment for HIV. Drug Metab Dispos 2005 Apr; 33: 587–95
Ramanathan S, Abel S, Tweedy S et al. Pharmacokinetic interaction of ritonavir-boosted elvitegravir and maraviroc. J Acquir Immune Defic Syndr 2010 Feb;53(2): 209–14
Abel S, Russell D, Taylor-Worth RJ, et al. Effects of CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers. Br J Clin Pharmacol 2008 Apr; 65 (Suppl. 1): 27–37
Selzentry (maraviroc) tablets: US prescribing information. New York: Pfizer Labs, 2010 May [online]. Available from URL: http://www.viivhealthcare.com/products/~/media/Files/G/GlaxoSmithKline-Plc/Attachments/pdfs/products/selzentry_maraviroc_tablets_5May2010.pdf [Accessed 2011 Jan 27]
Bertz R, Hsu A, Lam W, et al. Pharmacokinetic interactions between lopinavir-ritonavir (ABT-378r) and other non-HIV drugs [abstract no. P291 plus poster]. 5th International Congress on Drug Therapy for HIV Infection; 2000 Oct 22–26; Glasgow
Burger DM, Agarwala S, Child M, et al. Effect of rifampin on steady-state pharmacokinetics of atazanavir with ritonavir in healthy volunteers. Antimicrob Agents Chemother 2006 Oct;50(10): 3336–42
German P, West S, Hui J, et al. Pharmacokinetic interaction between elvite-gravir/ritonavir and dose-adjusted rifabutin [abstract no. 19 plus poster]. 9th International Workshop on Clinical Pharmacology of HIV Therapy; 2008 Apr 7–9; New Orleans (LA)
Song I, Patel A, Min S, et al. Evaluation of antacid and multivitamin (MVI) effects on S/GSK1349572 pharmacokinetics (PK) in healthy subjects [abstract no. plus poster]. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2009 Sep 12–15; San Francisco (CA)
Yong WP, Ramirez J, Innocenti F, et al. Effects of ketoconazole on glucuronidation by UDP-glucuronosyltransferase enzymes. Clin Cancer Res 2005 Sep;11(18): 6699–704
Zhao P, Ragueneau-Majlessi I, Zhang L, et al. Quantitative evaluation of pharmacokinetic inhibition of CYP3A substrates by ketoconazole: a simulation study. J Clin Pharmacol 2009; 49: 351–9
German P, Mathias A, West S, et al. Evaluation of ritonavir boosted elvitegravir pharmacokinetics upon coadministration with a second potent CYP3A inhibitor, ketoconazole [abstract no. 48 plus oral presentation]. 11th International Workshop on Clinical Pharmcology of HIV Therapy; 2010 Apr 7–9; Sorrento
Sekar VJ, Lefebvre E, De Pauw M, et al. Pharmacokinetics of darunavir/ ritonavir and ketoconazole following coadministration in HIV-healthy volunteers. Br J Clin Pharmacol 2008 Aug;66(2): 215–21
Wire MB, Ballow CH, Borland J, et al. Fosamprenavir plus ritonavir increases plasma ketoconazole and ritonavir exposure, while amprenavir exposure remains unchanged. Antimicrob Agents Chemother 2007 Aug;51(8): 2982–4
Acknowledgements
All authors are employees of Gilead Sciences, Inc. (Foster City, CA, USA), contributed significantly to the design, conduct, analyses and interpretation of data, and were involved in the preparation, review and approval of this article. Gilead Sciences, Inc. provided funding for the research presented in this article, except the single-dose, elvitegravir pharmacokinetic evaluation (administered alone), which was performed and funded by Japan Tobacco (Tokyo, Japan). Elvitegravir project team and individual study team members contributed towards the conduct and management of clinical trials described here. All authors are stockholders of Gilead Sciences, Inc.
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Ramanathan, S., Mathias, A.A., German, P. et al. Clinical Pharmacokinetic and Pharmacodynamic Profile of the HIV Integrase Inhibitor Elvitegravir. Clin Pharmacokinet 50, 229–244 (2011). https://doi.org/10.2165/11584570-000000000-00000
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DOI: https://doi.org/10.2165/11584570-000000000-00000