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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

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Pharmacokinetic Enhancers

Cobicistat

Last Updated: April 27, 2017; Last Reviewed: April 27, 2017

Cobicistat (COBI, TYBOST)
Cobicistat (COBI, TYBOST)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/daf/
Formulations
Tablets: 150 mg
Fixed-Dose Combination Tablets:
  • [Stribild] Elvitegravir 150 mg plus cobicistat 150 mg plus emtricitabine 200 mg plus tenofovir disoproxil fumarate 300 mg
  • [Genvoya] Elvitegravir 150 mg plus cobicistat 150 mg plus emtricitabine 200 mg plus tenofovir alafenamide 10 mg
  • [Evotaz] Atazanavir 300 mg plus cobicistat 150 mg
  • [Prezcobix] Darunavir 800 mg plus cobicistat 150 mg
Dosing Recommendations Selected Adverse Events
Cobicistat is a Pharmacokinetic (PK) Enhancer:
  • The only use of cobicistat is in adolescents and adults as a PK enhancer (boosting agent) of selected protease inhibitors (PIs) and the integrase inhibitor elvitegravir. Cobicistat is not interchangeable with ritonavir. See dosing information for specific PIs and elvitegravir that require cobicistat for boosting.
Pediatric Dosing
Not Food and Drug Administration (FDA)-Approved for Use in Children Aged <18 years:
  • Cobicistat alone (as Tybost)
  • Stribild
  • Evotaz
  • Prezcobix
  • Some Panel members consider that these agents may be appropriate in select children aged <18 years and weighing ≥35 kg; an expert in pediatric HIV infection should be consulted.
Not FDA-Approved for Use in Children Aged <12 Years or Weighing <35 kg:
  • Genvoya
  • Panel members consider that it may be appropriate to use Genvoya in children aged <12 years and weighing ≥35 kg; an expert in pediatric HIV infection should be consulted.
Child/Adolescent and Weighing ≥35 kg
  • Cobicistat 150 mg orally once daily as a component of Genvoya
Adult (Aged ≥18 Years) Dose:
  • Cobicistat must be administered as
    • The combination tablet Stribild or Genvoya, in which case it would not be dosed with any other antiretroviral (ARV) drugs; or
    • The tablet Tybost co-administered with atazanavir or darunavir at the doses listed in the table below and at the same time, in combination with other ARV drugs; or
    • Combination tablets with atazanavir (Evotaz) or darunavir (Prezcobix), with food, and in combination with other ARV drugs.

Cobicistat Dose Co-Administered Agent Dose Patient Population
150 mg orally once daily As part of Stribild or Genvoya; no other ARV drugs needed Treatment-naive or treatment-experienced with virus susceptible to all ARV drug components of Stribild or Genvoya
150 mg orally once daily Atazanavir 300 mg (co-formulated as Evotaz or given as a separate drug) orally once daily plus other ARV drugs Treatment-naive or treatment-experienced
150 mg orally once daily Darunavir 800 mg (co-formulated as Prezcobix or given as a separate drug) orally once daily plus other ARV drugs Treatment-naive or treatment-experienced with no darunavir-associated resistance mutations

  • When co-administered with TDF, cobicistat may be associated with higher risk of renal tubular adverse events than ritonavir.
Special Instructions
  • Cobicistat is not interchangeable with ritonavir.
  • Do not administer cobicistat with ritonavir or with drugs containing cobicistat.
  • Not recommended for use with more than one ARV drug that requires PK enhancement (e.g., elvitegravir in combination with a PI) because no data are available.
  • Use with PIs other than atazanavir 300 mg or darunavir 800 mg administered once daily is not recommended because no data are available on other combinations or doses.
  • Patients with a confirmed increase in serum creatinine >0.4 mg/dL from baseline should be closely monitored for renal safety.
  • When used in combinations with TDF, monitor serum creatinine, urine protein, and urine glucose at baseline and every 3 to 6 months while on therapy (see Table 12i). In patients at risk of renal impairment, also monitor serum phosphate.
  • When used in combination with other ARV drugs, see those specific sections of the appendix (atazanavir, darunavir, elvitegravir, TDF, TAF).
Metabolism/Elimination
  • Cytochrome P (CYP) 3A4 and CYP2D6 inhibitor
  • Cobicistat inhibits renal tubular secretion of creatinine, increasing the serum creatinine concentration (and decreasing estimated glomerular filtration rate) without decreasing actual glomerular function.
Dosing of Cobicistat in Patients with Renal Impairment:
  • Stribild should not be initiated in patients with estimated creatinine clearance (CrCl) <70 mL/min and should be discontinued in patients with estimated CrCl <50 mL/min because dose adjustments required for emtricitabine and TDF cannot be achieved with a fixed-dose combination tablet.
  • Genvoya should not be initiated in patients with estimated CrCl <30 mL/min.
  • Neither Stribild nor Genvoya should be used in patients with severe hepatic impairment.

Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and http://www.hiv-druginteractions.org/)

  • Metabolism: Cobicistat is an inhibitor of cytochrome P (CYP)3A4 and a weak inhibitor of CYP2D6; in addition, cobicistat inhibits adenosine triphosphate (ATP)-dependent transporters BCRP and P-glycoprotein and the organic anion transporting polypeptides OAT1B1 and OAT1B3. By inhibiting P-glycoprotein intestinal secretion, cobicistat increases the bioavailability of tenofovir alafenamide (TAF) by 2.2-fold, so the 10-mg dose of TAF in Genvoya is equivalent to the 25-mg dose of TAF found in other coformulated, TAF-containing preparations not containing cobicistat.1,2 The potential exists for multiple drug interactions when using cobicistat.
  • Before cobicistat is administered, a patient’s medication profile should be carefully reviewed for potential interactions and overlapping toxicities with other drugs.
  • Cobicistat and ritonavir are not interchangeable,3 and administration with either atazanavir or darunavir may result in different drug interactions when used with other concomitant medications.

Major Toxicities

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

Resistance

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

Pediatric Use

Approval
Cobicistat alone (as Tybost), or cobicistat coformulated with atazanavir (as Evotaz) or darunavir (as Prezcobix), or as a component of Stribild, is not Food and Drug Administration (FDA)-approved for use in children aged <18 years. Cobicistat as a component of Genvoya is FDA-approved at the adult dose in children aged ≥12 years and body weight ≥35 kg. The safety of cobicistat as a component of Genvoya in this age and weight group suggests the cobicistat component would be safe in other formulations, as well.4

References

  1. Ruane PJ, DeJesus E, Berger D, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. J Acquir Immune Defic Syndr. 2013;63(4):449-455. Available at http://www.ncbi.nlm.nih.gov/pubmed/23807155.
  2. Lepist EI, 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):5409-5413. Available at http://www.ncbi.nlm.nih.gov/pubmed/22850510.
  3. von Hentig N. Clinical use of cobicistat as a pharmacoenhancer of human immunodeficiency virus therapy. HIV/AIDS. 2016;8:1-16. Available at http://www.ncbi.nlm.nih.gov/pubmed/26730211.
  4. Cobicistat (Tybost) [package insert]. Food and Drug Administration. 2016. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203094s005lbl.pdf.

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