Abstract
Purpose
This article reviews the clinical pharmacology, pharmacodynamic and pharmacokinetic
(PK) properties, clinical efficacy and tolerability, drug interactions, and dosing
and administration of cobicistat.
Methods
Searches of MEDLINE and International Pharmaceutical Abstracts from 1964 to February
2015 were conducted using the search terms cobicistat and GS-9350. Relevant information was extracted from the identified clinical trials and review
articles. Abstracts from the Conference on Retroviruses and Opportunistic Infections
(2014–2015) and the Interscience Conference on Antimicrobial Agents and Chemotherapy
(2013–2014) were also searched.
Findings
Cobicistat is a PK enhancer lacking antiviral activity that, via selective cytochrome
P-450 (CYP) 3A inhibition, inhibits the metabolism of certain antiretroviral medications
and is used for prolonging their effect. Cobicistat has been studied as a booster
of elvitegravir, a second-generation integrase inhibitor, and of the protease inhibitors
atazanavir and darunavir. Data on its clinical efficacy and tolerability have been
presented in 2 Phase II trials and in 9 Phase III trials, which reported durable efficacy
in terms of achievement of sustained suppression of HIV-1 RNA levels to <50 copies/mL
for at least 48 weeks. Cobicistat was generally well-tolerated in these studies. Cobicistat
may increase serum creatinine levels via the inhibition of proximal renal tubular
cell transporters and thus reduce estimated glomerular filtration rate, although it
does not appear to affect actual glomerular filtration rate. Given the potent CYP3A
inhibition by cobicistat, its coadministration with drugs metabolized by CYP3A may
result in increased plasma concentrations of such agents. Moreover, as cobicistat
is metabolized predominantly by CYP3A, plasma concentrations may increase or decrease
on coadministration with CYP3A inhibitors or inducers, respectively.
Implications
With potent durability through 48 weeks, a tolerability profile comparable to other
first- and second-line antiretroviral therapies, and a convenient dosing schedule
with low daily pill burden in fixed-dose combination tablets, cobicistat is a potential
addition to the management of HIV infection as a PK enhancer. However, the effects
of cobicistat on serum creatinine and its considerable drug-interaction potential
may warrant additional monitoring.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical TherapeuticsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
Joint United Nations Programme on HIV/AIDS. Global Report: UNAIDS report on the global AIDS epidemic 2013. http://www.unaids.org/en/resources/campaigns/globalreport2013/globalreport. Accessed April 30, 2015.
- Monitoring selected national HIV prevention and care objectives by using HIV surveillance data—United States and 6 dependent areas—2012.HIV Surveillance Supplemental Report. 2014; 19: 3
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services. April 8, 2015; A1-P20. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed April 30, 2015.
Gilead Sciences, Inc. [press release]. Gilead submits new drug application to U.S. Food and Drug Administration for tenofovir alafenamide (TAF)-based single tablet regimen for HIV. http://www.gilead.com/news/press-releases/2014/11/gilead-submits-new-drug-application-to-us-food-and-drug-administration-for-tenofovir-alafenamide-tafbased-single-tablet-regimen-for-hiv. Accessed April 30, 2015.
Tybost [package insert]. Foster City, CA: Gilead Sciences, Inc; 2014. http://www.gilead.com/~/media/Files/pdfs/medicines/hiv/tybost/tybost_pi.pdf. Accessed April 30, 2015.
Stribild [package insert]. Foster City, CA: Gilead Sciences, Inc; 2014. http://www.gilead.com/~/media/Files/pdfs/medicines/hiv/stribild/stribild_pi.ashx. Accessed April 30, 2015.
- Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV type 1-infected patients: week 48 results.J Infect Dis. 2013; 208: 32-39
Norvir [package insert]. North Chicago, IL: AbbVie, Inc; 2015. http://www.rxabbvie.com/pdf/norvirtab_pi.pdf. Accessed August 17, 2015
- Cobicistat (GS-9350): A potent and selective inhibitor of human CYP3A as a novel pharmacoenhancer.ACS Med Chem Lett. 2010; 1: 209-213
- Pharmacokinetics and pharmacodynamics of GS-9350: A novel pharmacokinetic enhancer without anti-HIV activity.Clin Pharmacol Ther. 2010; 87: 322-329
- Toxicological significance of mechanism-based inactivation of cytochrome P450 enzymes by drugs.Crit Rev Toxicol. 2007; 37: 389-412
- Mechanism-based inactivation of human cytochrome P450 enzymes and the prediction of drug-drug interactions.Drug Metab Dispos. 2007; 35: 246-255
- Cobicistat boosts the intestinal absorption of transport substrates, including HIV protease inhibitors and GS-7340, in vitro.Antimicrob Agents Chemother. 2012; 56: 5409-5413
- 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; 55: 323-329
- Effects of a protein-rich drink or a standard meal on the pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir in healthy Japanese male subjects: A randomized, three-way crossover study.J Clin Pharmacol. 2014; 54: 640-648
Evotaz [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. http://packageinserts.bms.com/pi/pi_evotaz.pdf. Accessed April 30, 2015.
Prezcobix [package insert]. Titusville, NJ: Janssen Therapeutics; 2015. https://www.prezcobix.com/shared/product/prezcobix/prescribing-information.pdf. Accessed April 30, 2015.
- Metabolism and excretion in humans of the pharmacoenhancer GS-9350.Presented at: 11th International Workshop on Clinical Pharmacology of HIV Therapy. April 7-9, 2010; (Sorrento, Italy; Abstract 18)
- Pharmacokinetics and safety of boosted elvitegravir in subjects with hepatic impairment.Antimicrob Agents Chemother. 2014; 58: 2564-2569
- Pharmacokinetics of elvitegravir and cobicistat in subjects with severe renal impairment.Presented at: 13th International Workshop on Clinical Pharmacology of HIV Therapy. April 16-18, 2012; (Barcelona, Spain; Abstract P_38)
- Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection.AIDS. 2011; 25: F7-F12
- 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: 1881-1886
- Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: A randomised, double-blind, phase 3 trial, analysis of results after 48 weeks.Lancet. 2012; 379: 2439-2448
- A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: Analysis of week 96 results.J Acquir Immune Defic Syndr. 2013; 63: 96-100
- A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF versus single-tablet regimen efavirenz/emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: Analysis of week 144 results.J Acquir Immune Defic Syndr. 2014; 65: e118-e120
- Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: A randomised, double-blind, phase 3, non-inferiority trial.Lancet. 2012; 379: 2429-2438
- A randomized, double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus coformulated emtricitabine and tenofovir DF for initial treatment of HIV-1 infection: Analysis of week 96 results.J Acquir Immune Defic Syndr. 2013; 62: 483-486
- A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: Analysis of week 144 results.J Acquir Immune Defic Syndr. 2014; 65: e121-e124
- Cobicistat-boosted protease inhibitors in HIV-infected patients with mild to moderate renal impairment.HIV Clin Trials. 2014; 15: 269-273
- Cobicistat-boosted darunavir in HIV-1 infected adults: Week 48 results of a phase IIIb, open-label single-arm trial.AIDS Res Ther. 2014; 11: 39
- 48 week study of the first PI-based single tablet regimen (STR) darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) vs. cobicistat (COBI)-boosted darunavir (DRV) and emtricitabine/tenofovir disoproxil fumarate (F/TDF) in treatment-naïve (TN) adults.Presented at: 54th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 5-9, 2014; (Washington, D.C.; Abstract H-647c)
- Switching from twice-daily raltegravir plus tenofovir disoproxil fumarate/emtricitabine to once-daily elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate in virologically suppressed, HIV-1-infected subjects: 48 weeks data.HIV Clin Trials. 2014; 15: 51-56
- Simplification to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial.Lancet Infect Dis. 2014; 14: 581-589
- Switching to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of non-nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir in virologically suppressed adults with HIV (STRATEGY-NNRTI): 48 week results of a randomised, open-label, phase 3b non-inferiority trial.Lancet Infect Dis. 2014; 14: 590-599
- Week 144 resistance analysis of elvitegravir/cobicistat/emtricitabine/tenofovir DF versus atazanavir+ritonavir+emtricitabine/tenofovir DF in antiretroviral-naïve patients.HIV Clin Trials. 2014; 15: 218-230
- Subgroup analyses of 144-week efficacy and safety of elvitegravir/cobicistat/emtricitabine/tenofovir DF (EVG/COBI/FTC/TDF).Presented at: 54th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 5-9, 2014; (Washington, D.C.; Abstract H-642)
- Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function.J Acquir Immune Defic Syndr. 2012; 61: 32-40
European Medicines Agency. Tybost 150 mg film-coated tablets. Summary of product characteristics; 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002572/WC500153014.pdf. Accessed April 30, 2015.
- Pharmacokinetics of once-daily boosted elvitegravir when administered in combination with acid-reducing agents.J Acquir Immune Defic Syndr. 2013; 64: 45-50
- Cost-effectiveness of the once-daily efavirenz/emtricitabine/tenofovir tablet compared with the once-daily elvitegravir/cobicistat/emtricitabine/tenofovir tablet as first-line antiretroviral therapy in HIV-infected adults in the US.Clinicoecon Outcomes Res. 2013; 5: 437-445
Article info
Publication history
Published online: August 25, 2015
Accepted:
July 30,
2015
Identification
Copyright
© 2015 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
