Atazanavir/Cobicistat versus Rosuvastatin
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Study Design
In this randomized, fixed sequence, multi-cohort, open label, single center study, sixteen healthy subjects received the following treatments:
Atorvastatin 10 mg (ATOR) or Rosuvastatin 10 mg (ROS) on day 1, Darunavir/Cobcistat 800 mg/150 mg (DRV/COBI) on days 4-15 and Darunavir/Cobistat plus Atorvastatin or Rosuvastatin on day 16 in one arm; or Atorvastatin 10 mg or Rosuvastatin 10 mg on day 1, Atazanavir/Cobicistat 300mg/150mg (ATV/COBI) on days 4-13 and Atazanavir/Cobicistat plus Atorvastatin or Rosuvastatin on day 14.
Pharmacokinetic assessments were performed on the final days of each treatment period. Statistical comparisons of exposures were made using geometric least squares mean (GLSM) ratios and associated 90% confidence intervals (CI) and compared to no-effect bounds of 70-143% for all analytes and parameters with the exception of Cmax for ATOR and ROS that had bounds of 50-200%.
Study Results
When coadministered with DRV/COBI, AUCinf and Cmax were increased by 93% and 277% for ROS, and 290% and 319% for ATOR, respectively. The AUCinf and Cmax were increased by 242% and 958% for ROS, and 822% and 1785% for ATOR, respectively when administered with ATV/COBI. ATOR and ROS did not affect DRV, ATV or COBI exposures. All subjects completed the study, and treatments were generally well tolerated. The majority of adverse events (AEs) that were related to study drug were mild in severity and no Grade 3 or 4 AEs were observed.
Study Conclusions
The authors concluded that the study findings backed the current dosing recommendations of atorvastatin or rosuvastatin with cobicistat boosted darunavir or atazanavir due to the inhibitor effect of atazanavir on OATP1B1/1B3 and inhibition of CYP3A and BCRP by cobicistat boosted darunavir or atazanaivr. As such, when DRV+COBI is coadministered with ROS or ATOR, it is recommended to initiate ROS or ATOR treatment with the lowest dose, and titrate to desired response while monitoring for safety. For ATV+COBI when coadministered with ROS, the lowest ROS dose is recommended while monitoring for safety. With respect to ATV+COBI, it is recommended not to exceed a single dose of 10 mg ATOR daily and monitor for safety.
References
Custodio J, West S, Gupta D, Zari A, Humeniuk R, Ling K. Evaluation of the drug-drug interaction potential between cobicistat-boosted protease inhibitors and statins. International Workshop On Clinical Pharmacology Of Antiviral Therapy. Chicago, IL, USA. 18; June 2017.
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