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Cobicistat
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Class
Background
U.S. Manufacturer
Approval
Formulation and Dosing
Clinical Use
Use in Initial vs Subsequent Therapy
Adverse Effects
Interactions with Other Drugs
Resistance
References
Related Resources
DHHS Guidelines
Characteristics of Integrase Inhibitors
Drug Interactions with Integrase Inhibitors
Adverse Events of ARVs
Dosage Adjustments for ARV-ARV Drug Interactions (Adult Dosing)
Interactions Database
Stanford Resistance Figures/Notes
Drug Labeling (Package Insert)
Cobicistat
Class

Pharmacokinetic enhancer

Background
U.S. Manufacturer

Gilead Sciences

Approval

Cobicistat is a pharmacokinetic enhancer that has no activity against HIV. It was granted approval by the U.S. Food and Drug Administration (FDA) in August 2012 as part of a coformulation that also includes the integrase inhibitor elvitegravir and the two nucleoside/nucleotide analogues (NRTIs) tenofovir and emtricitabine. In this fixed-dose coformulation, it is intended for use in initial therapy of adults with HIV-1 infection. Cobicistat has not been approved for use as a free-standing agent.

Approval was based primarily on 48-week results of 2 Phase III studies showing that previously untreated individuals who received elvitegravir/cobicistat/tenofovir/emtricitabine had rates of viral suppression and CD4 T-cell increases that were similar to those of individuals who received efavirenz + NRTIs or atazanavir+ ritonavir + 2 NRTIs.(1,2)

Formulation and Dosing

Cobicistat is available only in a fixed-dose combination tablet formulation with elvitegravir, tenofovir, and emtricitabine (Stribild).

Dosing of Cobicistat
AdultIn fixed-dose combination tablet:
Elvitegravir 150 mg + cobicistat 150 mg + tenofovir 300 mg + emtricitabine 200 mg, QD, 1 tablet QD (fixed-dose combination tablet)
PediatricNot FDA approved

Abbreviations: QD = once daily

Cobicistat should be taken with food.
Cobicistat interacts with a number of antiretroviral medications; see product labeling for further information.
The fixed-dose combination elvitegravir/cobicistat/tenofovir/emtricitabine should not be initiated in patients with CrCl <70 mL/min and should be discontinued in those with CrCl <50 mL/min.
Dosage adjustment for mild or moderate hepatic impairment is not required. No data are available to guide use in persons with severe liver disease.
Consult product labeling for detailed dosing information.
FDA Pregnancy Category B.

Clinical Use

Cobicistat is an inhibitor of cytochrome P450 3A (CYP3A) enzymes. It has no activity against HIV but is intended for use as a pharmacokinetic enhancer of antiretroviral agents that are metabolized by these enzymes (eg, the integrase inhibitor elvitegravir and certain protease inhibitors).

Use in Initial vs Subsequent Therapy

Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate cobicistat in combination with elvitegravir + tenofovir + emtricitabine as an "alternative" regimen for use in initial treatment of HIV infection.

In a Phase III study of initial treatment, cobicistat was compared with ritonavir as a pharmacokinetic enhancer of atazanavir, each combination given with tenofovir and emtricitabine. At week 48, by snapshot analysis, rates of HIV suppression to <50 copies/mL were 85% in the atazanavir + cobicistat group and 87% in the atazanavir + ritonavir group; the difference was not statistically significant.(1) An earlier Phase II study also compared cobicistat with ritonavir in combination with atazanavir plus tenofovir/emtricitabine in treatment-naive patients. At 48 weeks, by intention-to-treat analysis, HIV RNA was suppressed to <50 copies/mL in 82% of the cobicistat group and 86% of the ritonavir group; CD4 cell increases were 230 cells/µL and 206 cells/µL, respectively.(2)

In 2 Phase III studies in antiretroviral-naive adults, cobicistat was used as a pharmacokinetic enhancer of elvitegravir. In the first, the fixed-dose coformulation of elvitegravir/cobicistat/tenofovir/emtricitabine was compared with atazanavir + ritonavir + tenofovir/emtricitabine.(3) By snapshot analysis, 89.5% of elvitegravir + cobicistat recipients and 87% of atazanavir+ ritonavir recipients had HIV RNA suppression to <50 copies/mL at 48 weeks; the difference was not statistically significant. In the second study, elvitegravir/cobicistat/tenofovir/emtricitabine was compared with efavirenz/tenofovir/emtricitabine.(4) By snapshot analysis, 88% of elvitegravir + cobicistat recipients and 84% of efavirenz recipients had HIV RNA levels of <50 copies/mL at 48 weeks; the difference was not statistically significant. Mean CD4 increases were similar in the different treatment groups.

Cobicistat has not been studied in treatment-experienced patients.

Adverse Effects

Symptomatic side effects of cobicistat include nausea, diarrhea, and fatigue. When given with atazanavir, it increases the likelihood of icterus.

Cobicistat inhibits renal tubular secretion of creatinine and increases serum creatinine levels, resulting in a decrease in estimated glomerular filtration rate (GFR) without a true decline in GFR.(5) In Phase II and III studies, mean elevations in serum creatinine of approximately 0.14 mg/dL (and mean decreases in estimated GFR of approximately 14 mL/min) were observed in the first 2 weeks of treatment and remained stable to 48 weeks.(1,2,3,4,6) Cases of acute renal failure and Fanconi syndrome have been reported in patients given the fixed-dose combination elvitegravir/cobicistat/tenofovir/emtricitabine.(4,6) All study subjects also received tenofovir, an NRTI with known potential for renal toxicity; the relative roles of cobicistat, tenofovir, and other factors are not clear. Also, optimal clinical practices for distinguishing benign effects of cobicistat on creatinine (and estimated GFR) from true declines in renal function have not been established; monitoring of renal parameters is recommended. Cobicistat has not been well studied in individuals with CrCl <70 mL/min, and initiation in these persons is not recommended.

It is important to assess patient motivation and discuss possible adverse effects and strategies for their management before treatment with cobicistat is initiated.

Cobicistat has not been studied in pregnant women; it is classified as an FDA Pregnancy Category B drug.

Interactions with Other Drugs

Cobicistat is an inhibitor of cytochrome P450 3A (CYP3A) and 2D6 (CYP2D6) enzymes as well as an inhibitor of cellular transporters p-glycoprotein, BCRP, OATP1B1, and OATP1B3. Thus, cobicistat may cause clinically significant alterations in serum levels of a variety of other drugs, including other antiretrovirals, that are metabolized by or are substrates of these systems. Management of most of these interactions has not been established.

For example, cobicistat may increase levels of certain calcium channel blockers, beta-blockers, HMG-CoA reductase inhibitors (statins), antiarrhythmics, sedative-hypnotics, erectile dysfunction agents, inhaled corticosteroids, and norgestimate. It increases serum levels of the integrase inhibitor elvitegravir and of several protease inhibitors including atazanavir and darunavir.(1,2,3,4,6,7,8) It is FDA approved as a pharmacokinetic enhancer of elvitegravir (in the elvitegravir/cobicistat/tenofovir/emtricitabine coformulation), and has been studied clinically as a pharmacokinetic booster of atazanavir.(1,2) However, pending additional studies, concurrent administration of elvitegravir/cobicistat/tenofovir/emtricitabine with other antiretrovirals is not recommended.

Cobicistat in turn is metabolized by CYP3A and CYP2D6, so drugs that induce or inhibit the action of this isoenzyme may alter serum cobicistat concentrations. Azole antifungals and clarithromycin may increase serum cobicistat concentrations (and cobicistat may simultaneously increase serum levels of the coadministered antimicrobial). Rifabutin and some antiepileptic medications (eg, carbamazepine and phenytoin) are among the medications that may decrease cobicistat levels.

Adequate pharmacokinetic data and clinical correlates are not yet available for many potential interactions. Information on drug interactions should be consulted, as dosage adjustments are frequently required and some combinations are contraindicated.

For additional information, see the Database of Antiretroviral Drug Interactions.

Resistance

Cobicistat has no activity against HIV and thus does not select for resistance mutations.

References
1.  Gallant J, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as pharmacoenhancers in combination with atazanavir plus tenofovir disoproxil fumarate/emtricitabine: phase 3 randomized, double blind, active-controlled trial, week 48 results. In: Program and abstracts of the XIX International AIDS Conference; July 22-27, 2012; Washington. Abstract TUAB0103.
2.   Elion R, Cohen C, Gathe J, et al; GS-US-216–0105 Study Team. 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 Sep 24;25(15):1881-6.
3.   DeJesus E, Rockstroh JK, Henry K, et al; GS-236-0103 Study Team. 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 Jun 30;379(9835):2429-38.
4.   Sax PE, DeJesus E, Mills A, et al; GS-US-236-0102 Study Team. 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 Jun 30;379(9835):2439-48.
5.   German P, Liu HC, Szwarcberg J, et al. Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function. J Acquir Immune Defic Syndr. 2012 Sep 1;61(1):32-40.
6.  Stribild [prescribing information]. Gilead Sciences: Foster City, CA; August 2012.
7.  Kakuda TN, Opsomer M, Timmers M, et al. Bioavailability of two FDC formulations of darunavir/cobicistat 800/150 mg compared with darunavir/ritonavir 800/100 mg coadministered as single agents. In: Program and abstracts of the 13th International Workshop on Clinical Pharmacology of HIV Therapy; April 16-18, 2012; Barcelona. Abstract O_20.
8.  Ramanathan S, Wang H, Szwarcberg J, et al. Safety/tolerability, pharmacokinetics and boosting of twice-daily cobicistat administered alone or in combination with darunavir or tipranavir. In: Program and abstracts of the 13th International Workshop on Clinical Pharmacology of HIV Therapy; April 16-18, 2012; Barcelona. Abstract P_08.