Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States

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Pharmacoenhancers

Cobicistat (Tybost, COBI)

Last Updated: November 14, 2017; Last Reviewed: November 14, 2017

Cobicistat has insufficient data on human use in pregnancy to inform a drug-associated risk determination for birth defects or miscarriage.

Animal Studies 

Carcinogenicity
At cobicistat exposures 7 times and 16 times the human systemic exposure, no increases in tumor incidence were seen in male and female mice. In rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses up to twice the typical human exposure. The follicular cell findings are considered rat-specific, and not relevant to humans.1

Reproduction/Fertility
No effect has been seen on fertility in male or female rats.1

Teratogenicity/Adverse Pregnancy Outcomes
Rats and rabbits treated with cobicistat during pregnancy at 1.4 and 3.3 times higher than the recommended human exposure have shown no evidence of teratogenicity.

Placental and Breast Milk Passage
No information is available on placental passage of cobicistat. Studies in rats have shown that cobicistat is secreted in breast milk.2

Human Studies in Pregnancy 

Pharmacokinetics
A single case report found that cobicistat area under the curve (AUC) was reduced by 44% during the third trimester of pregnancy.3 A recent abstract described cobicistat pharmacokinetics (PK) in paired third-trimester and postpartum evaluations from 15 pregnant women taking concomitant elvitegravir. Cobicistat AUC was significantly reduced by 57% in the third trimester. Post-dose concentrations (at 24 hours) were reduced by at least 76%; cobicistat was below detection (<10 ng/mL) in most trough samples in pregnancy. Oral clearance of cobicistat was more than doubled during pregnancy.4 The pharmaco-enhancing effect of cobicistat on elvitegravir was impacted during pregnancy; elvitegravir AUC was reduced by 42% and trough concentrations were reduced by 87% in the third trimester compared to postpartum. No data are available on the impact of pregnancy on the pharmaco-enhancing activity of cobicistat for other coadministered antiretroviral drugs during pregnancy, such as darunavir or atazanavir.

Placental and Breast Milk Passage
No data are available on breast milk passage of cobicistat in humans. A study in 10 women found a median cord/maternal plasma concentration ratio of 0.09. This study also found measurable concentrations of cobicistat in placental tissue and cord blood peripheral blood mononuclear cells (PBMC), with a cord/maternal PBMC ratio of 0.49.5  In 16 neonates, cobicistat was below detection in all washout PK samples taken between 2 hours and 9 days post-delivery.4

Teratogenicity/Adverse Pregnancy Outcomes
In the Antiretroviral Pregnancy Registry, 1 birth defect has been reported in 83 live births with first-trimester exposure. The number of first-trimester exposures to cobicistat in humans is insufficient to be able to make a risk determination.2

Excerpt from Table 9a
Generic Name
(Abbreviation)
Trade Name
Formulation Dosing Recommendations Use in Pregnancy
Cobicistat
(COBI)
Tybost

Elvitegravir/Cobicistat/Tenofovir Disoproxil Fumarate/Emtricitabine
(EVG/COBI/TDF/FTC)
Stribild

Elvitegravir/Cobicistat/Tenofovir Alafenamide/Emtricitabine
(EVG/COBI/TAF/FTC)
Genvoya

Atazanavir/Cobicistat
(ATV/COBI)
Evotaz

Darunavir/Cobicistat
(DRV/COBI)
Prezcobix
Tablet (Tybost):
  • 150 mg
Tablet (Stribild):
  • EVG 150 mg plus COBI 150 mg plus TDF 300 mg plus FTC 200 mg
Tablet (Genvoya):
  • EVG 150 mg plus COBI 150 mg plus TAF 10 mg plus FTC 200 mg
Tablet (Evotaz):
  • ATV 300 mg plus COBI 150 mg
Tablet (Prezcobix):
  • DRV 800 mg plus COBI 150 mg
Standard Adult Dose
Tybost:
  • As an alternative PK booster with ATV or DRV/r: 1 tablet (150 mg) once daily with food.
Stribild, Genvoya, Evotaz, Prezcobix:
  • 1 tablet once daily with food.
PK in Pregnancy:
  • Based on limited data, cobicistat exposure and pharmaco-enhancing effect are markedly reduced in pregnancy.
Dosing in Pregnancy:
  • While COBI exposure is markedly reduced during pregnancy, higher than standard doses have not been studied. The Panel recommends the use of RTV as the preferred pharmaco-enhancer during pregnancy until more data are available on COBI activity during pregnancy.
Low placental transfer to fetus.b

Insufficient data to assess for teratogenicity in humans. No evidence of teratogenicity in rats or rabbits.
a Individual antiretroviral drug dosages may need to be adjusted in renal or hepatic insufficiency (for details, see the Adult and Adolescent Guidelines Appendix B, Table 7).
b Placental transfer categories—Mean or median cord blood/maternal delivery plasma drug ratio:
          High: >0.6
          Moderate: 0.3–0.6
          Low: <0.3
c See Teratogenicity section for discussion of EFV and risks in pregnancy.
d Only indicated for use in chronic hepatitis B virus infection in adults
e Generic formulation available

Key to Acronyms: ATV = atazanavir; COBI = cobicistat; DRV = darunavir; DRV/r = darunavir/ritonavir; EFV = efavirenz; EVG = elvitegravir; FTC = emtricitabine; PK = pharmacokinetic; RTV = ritonavir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate

References

  1. Cobicistat [package insert]. Food and Drug Administration. 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203094s007lbl.pdf.
  2. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989–31 July 2016. Wilmington, NC: Registry Coordinating Center. 2016. Available at http://www. apregistry.com/.
  3. Schalkwijk S, Colbers A, Konopnicki D, et al. First reported use of elvitegravir and cobicistat during pregnancy. AIDS. 2016;30(5):807-808. Available at http://www.ncbi.nlm.nih.gov/pubmed/26913711.
  4. Best B, Caparelli E, Stek A, et al. Elvitegravir/cobicistat pharmacokinetics in pregnancy and postpartum. Presented at: Conference on Retroviruses and Opportunistic Infections. 2017. Seattle, WA.
  5.  Rimawi BH, Johnson E, Rajakumar A, et al. Pharmacokinetics and Placental Transfer of Elvitegravir and Dolutegravir, and Other Antiretrovirals during Pregnancy. Antimicrob Agents Chemother. 2017. Available at https://www.ncbi.nlm.nih.gov/pubmed/28348149.
     

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