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Statin Levels Much Higher With Cobicistat-Boosted Atazanavir or Darunavir
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18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago
Mark Mascolini
Concentrations of the antilipid agents atorvastatin and rosuvastatin rose substantially when given with atazanavir/cobicistat or darunavir/cobicistat [1]. Results of this study in healthy volunteers support current conservative dosing recommendations when giving statins with cobicistat-boosted atazanavir or darunavir.
Fixed-dose combinations of atazanavir/cobicistat (Evotaz) and darunavir/cobicistat (Prezcobix) are emerging as popular protease inhibitor (PI) options. Because of the inhibitory activity of cobicistat and these PIs on drug-metabolizing enzymes, Gilead researchers hypothesized that the boosted PIs would raise statin exposure.
The investigators noted that cobicistat inhibits CYP3A, P-gp, BCRP, and OATP1B1/1B3. Atazanavir inhibits CYP3A, UGT1A1, P-gp, BCRP, and OATP1B1/1B3. Darunavir inhibits CYP3A and P-gp. Statins are substrates for P-gp, BCRP, and OATP1B1/1B3. Atorvastatin is also metabolized by CYP3A.
In this three-period fixed-sequence open-label study, 16 healthy volunteers per cohort received the following agents:
Day 1: Atorvastatin or rosuvastatin (10 mg)
Days 4-13: Atazanavir/cobicistat (300/150 mg), or
Days 4-15: Darunavir/cobicistat (800/150 mg)
Day 14: Atazanavir/cobicistat (300/150 mg) plus atorvastatin or rosuvastatin (10 mg), or
Day 16: Darunavir/cobicistat (800/150mg) plus atorvastatin or rosuvastatin (10 mg)
The researchers measured drug levels on the final day of each treatment period. They used geometric least-squares mean (GLSM) ratios and 90% confidence intervals (CI) to compare drug levels alone or in combination. For atorvastatin and rosuvastatin maximum concentrations (Cmax), the no-effect bounds were 50% to 200%. For all other parameters the no-effect bounds were 70% to 143%.
All volunteers completed the entire study, and no grade 3 or 4 adverse events emerged. The two statins had no impact on exposure of darunavir, atazanavir, or cobicistat.
For all PI-on-statin interactions analyzed, the GLSM ratios and 90% CIs fell outside predetermined no-effect bounds, a result indicating interactions between each of the boosted PIs and each of the statins.
Rosuvastatin area under the concentration-time curve (AUC) rose 93% and Cmax 277% with darunavir/cobicistat. Atorvastatin AUC climbed 290% and Cmax 319% with darunavir/cobicistat. Rosuvastatin AUC rose 242% and Cmax 958% with atazanavir/cobicistat. Atorvastatin AUC jumped 822% and Cmax 1790% with atazanavir/cobicistat. The Gilead team noted that these results reflect atazanavir inhibition of OATP1B1/1BC, atazanavir/cobicistat inhibition of CYP3A and BCRP, and darunavir/cobicistat inhibition of CYP3A and BCRP.
The investigators believe their findings support current atorvastatin and rosuvastatin dosing recommendations with cobicistat-boosted darunavir [2] or atazanavir [3]. With darunavir/cobicistat, each statin should start at the lowest dose, which is raised to attain the desired response with close monitoring for safety. With atazanavir/cobicistat, the researchers recommend that the lowest rosuvastatin dose should be used while monitoring closely for safety, and the atorvastatin dose should not exceed 10 mg daily.
References
1. Custodio J, West S, SenGupta D, et al. Evaluation of the drug-drug interaction potential between cobicistat-boosted protease inhibitors and statins. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago. Abstract O_04.
2. Darunavir/cobicistat prescribing information:
https://www.prezcobixhcp.com/sites/www.prezcobix.com-hcp/files/prescribing-information-prezcobix.pdf
3. Atazanavir/cobicistat prescribing information: http://packageinserts.bms.com/pi/pi_evotaz.pdf
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