Skip to main content
SpringerLink
Log in

Cobicistat: A Review of Its Use as a Pharmacokinetic Enhancer of Atazanavir and Darunavir in Patients with HIV-1 Infection

  • Adis Drug Evaluation
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Cobicistat (Tybost™) is a mechanism-based inhibitor of cytochrome P450 (CYP) 3A enzymes that is indicated in the EU as a pharmacokinetic enhancer (i.e. booster) of the HIV-1 protease inhibitors (PIs) atazanavir and darunavir in adults. Cobicistat has a lower potential for off-target drug interactions than the standard boosting agent ritonavir, due to its more selective inhibition of CYP3A and lower likelihood for enzymatic induction, and is devoid of anti-HIV activity. When used to boost darunavir or atazanavir in healthy volunteers, oral cobicistat 150 mg once daily provided bioequivalent PI exposure to that seen with oral ritonavir 100 mg once daily (i.e. low-dose ritonavir). Moreover, in treatment-naïve adults infected with HIV-1 participating in a large, double-blind, phase III trial, an atazanavir-based antiretroviral regimen boosted with cobicistat 150 mg once daily provided a high rate of virological suppression after 48 weeks of therapy that was noninferior to that seen with low-dose ritonavir boosting. Cobicistat was generally well tolerated in this study, with a tolerability profile similar to that of ritonavir. Cobicistat may increase serum creatinine levels (possibly via inhibition of proximal renal tubular cell transporters) and thus reduce estimated glomerular filtration rate (GFR), although it does not appear to affect actual GFR. The drug is more soluble than ritonavir, making coformulation easier, and fixed-dose formulations combining cobicistat with darunavir and atazanavir are in development. Thus, cobicistat is an emerging alternative to ritonavir for the pharmacokinetic enhancement of PIs in adults with HIV-1 infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Williams I, Churchill D, Anderson J, et al. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012. HIV Med. 2012;13 Suppl 2:1–85. Plus update available at http://www.bhiva.org/documents/Conferences/Autumn2013/presentations/131114/DuncanChurchill.pdf. Accessed 26 Nov 2013.

  2. European AIDS Clinical Society. Guidelines version 7.0, October 2013. 2013. http://www.eacsociety.org/Portals/0/Guidelines_Online_131014.pdf. Accessed 19 Nov 2013.

  3. Arts EJ, Hazuda DJ. HIV-1 antiretroviral drug therapy. Cold Spring Harb Perspect Med. 2012;2(4):a007161.

    Article  PubMed  Google Scholar 

  4. Gras J. Cobicistat. Cytochrome P450 CYP3A inhibitor, anti-HIV agent. Drugs Future. 2012;37(5):315–24.

    CAS  Google Scholar 

  5. Arya V, Robertson SM, Struble KA, et al. Scientific considerations for pharmacoenhancers in antiretroviral therapy. J Clin Pharmacol. 2012;52(8):1128–33.

    Article  CAS  PubMed  Google Scholar 

  6. Kuritzkes DR. Drug resistance in HIV-1. Curr Opin Virol. 2011;1(6):582–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Josephson F. Drug-drug interactions in the treatment of HIV infection: focus on pharmacokinetic enhancement through CYP3A inhibition. J Intern Med. 2010;268(6):530–9.

    Article  CAS  PubMed  Google Scholar 

  8. Shah BM, Schafer JJ, Priano J, et al. Cobicistat: a new boost for the treatment of human immunodeficiency virus infection. Pharmacotherapy. 2013. doi:10.1002/phar.1237.

  9. Breitenbach J. Melt extrusion can bring new benefits to HIV therapy. Am J Drug Deliv. 2006;4(2):61–4.

    Article  CAS  Google Scholar 

  10. Mascolini M. What will it take to replace ritonavir as the prime PK booster? Debate ritonavir v GS9350 [conference report]. 11th International Workshop on Clinical Pharmacology of HIV Therapy; 7–9 Apr 2010; Sorrento.

  11. Gilead Sciences International Ltd. Tybost 150 mg film-coated tablets: EU summary of product characteristics. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002572/WC500153014.pdf. Accessed 19 Nov 2013.

  12. Gilead. Gilead’s boosting agent cobicistat for HIV therapy as effective as ritonavir in pivotal phase 3 study [media release]. 24 Jul 2012. http://investors.gilead.com/phoenix.zhtml?c=69964&p=irol-newsArticle_pf&id=1717796.

  13. Gilead Sciences Inc. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) tablets, for oral use: US prescribing information. 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203100s009lbl.pdf. Accessed 19 Nov 2013.

  14. Gilead Sciences International Ltd. Stribild 150 mg/150 mg/200 mg/245 mg film-coated tablets: EU summary of product characteristics. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002574/WC500144272.pdf. Accessed 19 Nov 2013.

  15. Perry CM. Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen (Stribild): a review of its use in the management of HIV-1 infection in adults. Drugs. 2013. doi:10.1007/s40265-013-0158-4.

  16. Callebaut C, Tsai L, Stray K, et al. Biological profiling of GS-9350, a novel pharmacoenhancer that lacks anti-HIV activity and exhibits low potential for metabolic adverse effects in vitro [abstract]. Antivir Res. 2010;86(1):A31.

    Article  Google Scholar 

  17. Lepist EI, Murray BP, Tong L, et al. Effect of cobicistat and ritonavir on proximal renal tubular cell uptake and efflux transporters [abstract no. A1-1724 plus poster]. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy; 17–20 Sept 2011; Chicago (IL).

  18. Post F, Andrade-Villanueva J, Fisher M, et al. Renal safety of elvitegravir/cobicistat/emtricitabine/tenofovir DF (STB) and cobicistat-boosted protease inhibitor regimens in HIV-1-infected patients with mild to moderate renal impairment [abstract no. TUPE280 plus poster]. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; 30 June–3 July 2013; Kuala Lumpur.

  19. Ramanathan S, Warren D, Wei L, et al. Pharmacokinetic boosting of atazanavir with the pharmacoenhancer GS-9350 versus ritonavir [poster A1-1301]. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; 12–15 Sep 2009; San Francisco (CA).

  20. German P, Wei X, Mizuno V, et al. Pharmacokinetics of elvitegravir and cobicistat in subjects with severe renal impairment [abstract no. P_38]. 13th International Workshop on Clinical Pharmacology of HIV Therapy; 16–18 April 2012; Barcelona.

  21. Xu L, Liu H, Murray BP, et al. Cobicistat (GS-9350): a potent and selective inhibitor of human CYP3A as a novel pharmacoenhancer. ACS Med Chem Lett. 2010;1(5):209–13.

    Article  CAS  Google Scholar 

  22. Mathias AA, German P, Murray BP, et al. Pharmacokinetics and pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without anti-HIV activity. Clin Pharmacol Ther. 2010;87(3):322–9.

    Article  CAS  PubMed  Google Scholar 

  23. Elion R, Cohen C, Gathe J, et al. Phase 2 study of cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose emtricitabine/tenofovir df in the initial treatment of HIV infection. AIDS. 2011;25(15):1881–6.

    Article  CAS  PubMed  Google Scholar 

  24. Gallant JE, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results. J Infect Dis. 2013;208(1):32–9.

    Article  CAS  PubMed  Google Scholar 

  25. German P, Liu HC, Szwarcberg J, et al. Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function. JAIDS. 2012;61(1):32–40.

    CAS  PubMed  Google Scholar 

  26. Custodio JM, Gordi T, Jin F, et al. A large population pharmacokinetic evaluation of the influence of demographic and HIV disease factors on the pharmacokinetics of elvitegravir, cobicistat and tenofovir [abstract no. MOPE036]. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; 30 June–3 July 2013; Kuala Lumpur.

  27. Mathias A, Liu HC, Warren D, et al. Relative bioavailability and pharmacokinetics of darunavir when boosted with the pharmacoenhancer GS-9350 versus ritonavir [abstract no. 28]. 11th International Workshop on Clinical Pharmacology of HIV Therapy; 7–9 Apr 2010; Sorrento.

  28. Kakuda TN, van de Casteele T, Petrovic R, et al. Bioequivalence of darunavir (800mg) co-administered with cobicistat (150mg) as either a fixed-dose combination tablet or as single agents under fasted and fed conditions in healthy volunteers [abstract no. MOPE029 plus poster]. 7th International AIDS Society Conference on HIV Pathogenesis and Treatment; 30 June–3 July 2013; Kuala Lumpur.

  29. German P, Mathias A, Wei L, et al. The effect of cobicistat on cytochrome P450 2D6, 2B6 and p-glycoprotein using phenotypic probes [slide presentation]. 12th International Workshop on Clinical Pharmacology of HIV Therapy; 13–15 Apr 2011; Miami (FL).

  30. Kliewer SA, Goodwin B, Willson TM. The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr Rev. 2002;23(5):687–702.

    Article  CAS  PubMed  Google Scholar 

  31. Lepist E-I, Phan TK, Roy A, et al. Cobicistat boosts the intestinal absorption of transport substrates, including HIV protease inhibitors and GS-7340, in vitro. Antimicrob Agents Chemother. 2012;56(10):5409–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Stray KM, Bam RA, Birkus G, et al. Evaluation of the effect of cobicistat on the in vitro renal transport and cytotoxicity potential of tenofovir. Antimicrob Agents Chemother. 2013. doi:10.1128/AAC.00712-13.

  33. Ramanathan S, Mathias A, Wei X, et al. Pharmacokinetics of once-daily boosted elvitegravir when administered in combination with acid-reducing agents. JAIDS. 2013;64(1):45–50.

    CAS  PubMed  Google Scholar 

  34. Bruce RD, Winkle P, Custodio JM, et al. The pharmacokinetic and pharmacodynamic interactions between buprenorphine/naloxone and elvitegravir/cobicistat in subjects receiving chronic buprenorphine/naloxone treatment. J Acquir Immune Defic Syndr. 2013;63(4):480–4.

    Article  CAS  PubMed  Google Scholar 

  35. Gilead Sciences. Phase 3, randomized, double-blind study to evaluate the safety and efficacy of GS-9350-boosted atazanavir versus ritonavir-boosted atazanavir each administered with emtricitabine/tenofovir disoproxil fumarate in HIV-1 infected antiretroviral treatment-naive adults [ClinicalTrials.gov identifier NCT01108510]. US National Institutes of Health, ClinicalTrials.gov. 2012. http://www.clinicaltrials.gov. Accessed 19 Nov 2013.

  36. Croom KF, Dhillon S, Keam SJ. Atazanavir: a review of its use in the management of HIV-1 infection. Drugs. 2009;69(8):1107–40.

    Article  CAS  PubMed  Google Scholar 

  37. Gilead Sciences International Ltd. Viread: EU summary of product characteristics. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000419/WC500051737.pdf. Accessed 19 Nov 2013.

  38. Cahn P, Sued O. Boosting HIV treatment options: good news, new challenges. J Infect Dis. 2013;208(1):4–6.

    Article  PubMed  Google Scholar 

  39. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2013. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Accessed 19 Nov 2013. Plus update available from http://aidsinfo.nih.gov/news/1392/hhs-panel-on-antiretroviral-guidelines-for-adults-and-adolescents-updates-recommendations-on-preferred-insti-based-regimens-for-art-naive-individuals. Accessed 26 Nov 2013.

  40. Gilead Sciences. Phase 3b open-label, single arm study to evaluate the safety and efficacy of cobicistat-boosted darunavir in HIV infected adults [ClinicalTrials.gov identifier NCT01440569]. US National Institutes of Health, ClinicalTrials.gov. 2011. http://www.clinicaltrials.gov. Accessed 19 Nov 2013.

  41. Coffey S. Cobicistat as a booster of atazanavir. 2012. http://hivinsite.ucsf.edu/InSite?page=hmq-1210-02. Accessed 7 Nov 2013.

  42. Stone VE, Jordan J, Tolson J, et al. Perspectives on adherence and simplicity for HIV-infected patients on antiretroviral therapy: self-report of the relative importance of multiple attributes of highly active antiretroviral therapy (HAART) regimens in predicting adherence. J Acquir Immune Defic Syndr. 2004;36(3):808–16.

    Article  PubMed  Google Scholar 

  43. Molina JM. Efficacy and safety of once-daily regimens in the treatment of HIV infection. Drugs. 2008;68(5):567–78.

    Article  CAS  PubMed  Google Scholar 

  44. Kaya S. HIV treatment with once-daily single tablet regimens. J Virol Antivir Res. 2013. doi:10.4172/2324-8955.1000105.

  45. Kakuda TN, Opsomer M, Trimmers M, et al. Bioavailability of two FDC formulations of darunavir/cobicistat 800/150mg compared with darunavir/ritonavir 800/100mg co-administered as single agent [abstract no. 0_20 plus slide presentation]. 13th International Workshop on Clinical Pharmacology of HIV Therapy; 16–18 Apr 2012; Barcelona.

Download references

Disclosure

The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit.

Author information

Authors and Affiliations

  1. Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, 0754, Auckland, New Zealand

    Emma D. Deeks

Authors
  1. Emma D. Deeks
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emma D. Deeks.

Additional information

The manuscript was reviewed by: B.M. Shah, Department of Pharmacy Practice, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA, USA; N. Von Hentig, Medical Department II, HIV Center, J. W. Goethe-University Hospital, Frankfurt, Germany.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Deeks, E.D. Cobicistat: A Review of Its Use as a Pharmacokinetic Enhancer of Atazanavir and Darunavir in Patients with HIV-1 Infection. Drugs 74, 195–206 (2014). https://doi.org/10.1007/s40265-013-0160-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-013-0160-x

Keywords

Search

Navigation