Pharmacokinetic Enhancers

Cobicistat

Drug Interactions

(See also the Adult and Adolescent Antiretroviral Guidelines and HIV Drug Interaction Checker)

• Metabolism: Metabolism of cobicistat (COBI) is mainly via cytochrome P450 (CYP) 3A4 and, to a lesser degree, CYP2D6. COBI is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. COBI also inhibits the breast cancer resistance protein, P-glycoprotein (P-gp), the organic anion transporting polypeptides OATP1B1 and OATP1B3, and multidrug and toxin extrusion 1 (MATE1). Unlike ritonavir (RTV), COBI does not demonstrate any enzyme-inducing effects. The potential exists for multiple drug interactions when using COBI. Before COBI is administered, a patient’s medication profile should be carefully reviewed for potential interactions and overlapping toxicities with other drugs.
• Nucleoside reverse transcriptase inhibitors: COBI is a strong P-gp inhibitor; thus, a dose of tenofovir alafenamide (TAF) 10 mg combined with COBI produces tenofovir (TFV) exposures that are similar to those produced by TAF 25 mg without COBI.² COBI increases plasma TFV exposures by 23% when it is coadministered with TDF; thus, renal safety should be monitored in patients who are receiving this combination.^1,3
• Non-nucleoside reverse transcriptase inhibitors: Efavirenz, etravirine, and nevirapine should not be used with COBI.
• Protease inhibitors: Using COBI as a dual booster for elvitegravir (EVG) and darunavir (DRV) has been studied in people with HIV and people without HIV, and the evidence is conflicting. When EVG plus COBI plus DRV was administered to people without HIV, the C_trough concentration of EVG was 50% lower than the C_trough concentration seen in people who received elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/c/FTC/TDF) without DRV.⁴ When EVG/c/FTC/TAF was administered with DRV to patients with HIV, both DRV and EVG concentrations were comparable to those seen in historic controls.⁵
• Integrase inhibitors: In one small study, dolutegravir (DTG) Ctrough concentrations were 107% higher when DTG was administered with darunavir/cobicistat (DRV/c) than when it was administered with darunavir/ritonavir.⁶ Bictegravir (BIC) area under the curve increases 74% when BIC is administered with DRV/c.⁷
• Corticosteroids: Increased serum concentrations of corticosteroids can occur when corticosteroids and COBI are coadministered; this can lead to clinically significant adrenal suppression. Adrenal suppression occurs regardless of whether the corticosteroids are administered orally or by some other route (e.g., intranasal, inhaled, interlaminar, intraarticular) and regardless of whether the corticosteroids are administered routinely or intermittently. A possible exception is beclomethasone, which appears to be a relatively safe option with inhaled or intranasal administration.^8,9

Major Toxicities

• More common: Nausea, vomiting, diarrhea, abdominal pain, anorexia.
• Less common (more severe): New onset renal impairment or worsening of renal impairment when used with TDF. Rhabdomyolysis; increased amylase and lipase levels.

Resistance

Not applicable. COBI has no antiviral activity. Its sole use is as a pharmacokinetic enhancer of antiretroviral drugs.

Pediatric Use

Approval
COBI, as a component of Stribild, is approved by the Food and Drug Administration (FDA) at the adult dose for use in children and adolescents aged ≥12 years and weighing ≥35 kg. The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel) recommends limiting the use of Stribild to those with a sexual maturity rating of 4 or 5. COBI, as a component of Genvoya, is approved by the FDA at the adult dose for use in children weighing ≥25 kg. COBI alone (as Tybost) is approved by the FDA at the adult dose for use in children weighing ≥35 kg when used in combination with ATV, and in children weighing ≥40 kg when used in combination with DRV. The FDA has not approved the use of COBI coformulated with ATV (as Evotaz) or DRV (as Prezcobix), or COBI as a component of Symtuza, in children aged <18 years. However, the Panel considers these fixed-dose combinations appropriate for pediatric use, given that the individual component drugs have been approved for use in children and adolescents who meet certain weight-based indications.

References

1. Tybost [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/203094s014lbl.pdf
2. Ramanathan S, Wei X, Custudio J, et al. Pharmacokinetics of a novel EVG/COBI/FTC/GS-7340 single tablet regimen. Abstract O-13. Presented at: International Workshop on Clinical Pharmacology of HIV Therapy. 2012. Barcelona, Spain. Available at: http://www.natap.org/2012/pharm/Pharm_24.htm.
3. Custodio J, Garner W, Jin F, et al. Evaluation of the drug interaction potential between the pharmacokinetic enhancer and tenofovir disoproxil fumarate in healthy subjects. Presented at: International Workshop on Clinical Pharmacology of HIV Therapy. 2013. Amsterdam, Netherlands.
4. Ramanathan S, Wang H, Szwarcberg J, Kearney BP. Safety/tolerability, pharmacokinetics, and boosting of twice-daily cobicistat administered alone or in combination with darunavir or tipranavir. Abstract P-08. Presented at: International Workshop on Clinical Pharmacology of HIV Therapy. 2012. Barcelona, Spain. Available at: http://www.natap.org/2012/pharm/Pharm_28.htm.
5. Gutierrez-Valencia A, Trujillo-Rodriguez M, Fernandez-Magdaleno T, Espinosa N, Viciana P, Lopez-Cortes LF. Darunavir/cobicistat showing similar effectiveness as darunavir/ritonavir monotherapy despite lower trough concentrations. J Int AIDS Soc. 2018;21(2). Available at: https://www.ncbi.nlm.nih.gov/pubmed/29430854.
6. Gervasoni C, Riva A, Cozzi V, et al. Effects of ritonavir and cobicistat on dolutegravir exposure: when the booster can make the difference. J Antimicrob Chemother. 2017;72(6):1842-1844. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28333266.
7. Zhang H, Custudio J, Wei X, et al. Clinical Pharmacology of the HIV integrase strand transfer inhibitor bictegravir. Abstract 40. Presented at: Conference on Retrovirsues and Opportunistic Infections. 2017. Seattle, Washington. Available at: http://www.croiconference.org/sessions/clinical-pharmacology-hiv-integrase-strand-transfer-inhibitor-bictegravir.
8. Saberi P, Phengrasamy T, Nguyen DP. Inhaled corticosteroid use in HIV-positive individuals taking protease inhibitors: a review of pharmacokinetics, case reports and clinical management. HIV Med. 2013;14(9):519-529. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23590676.
9. Boyd SD, Hadigan C, McManus M, et al. Influence of low-dose ritonavir with and without darunavir on the pharmacokinetics and pharmacodynamics of inhaled beclomethasone. J Acquir Immune Defic Syndr. 2013;63(3):355-361. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23535292.