Cobicistat as a PK Booster of Atazanavir
October 5, 2012
Cobicistat is a derivative of ritonavir and a potent inhibitor of CYP3A. As does ritonavir, it "boosts" blood levels of other substrates of this enzyme but, unlike ritonavir, it has no activity against HIV. It has been developed as a pharmacokinetic enhancer of the integrase inhibitor elvitegravir and of some PIs.
At the recent IAS conference, researchers presented results of a Phase 3 comparison of cobicistat (150 mg once daily) and ritonavir (100 mg once daily), each given in combination with atazanavir + tenofovir/emtricitabine in ARV-naive subjects. At week 48, rates of HIV suppression to <50 copies/mL were similar in the two groups (85% and 87%, respectively), meeting the study criteria for noninferiority of cobicistat. There were no differences between the groups in those with baseline HIV RNA levels of >100,000 copies/mL. In subjects with virologic failure, no PI mutations were seen (2 subjects in the cobicistat group developed the M184V mutation). CD4 increases were nearly identical. The frequency and types of adverse effects also were very similar (in particular, nausea, diarrhea, and bilirubin elevations), though elevations in creatinine were higher in the cobicistat group, caused by tubular inhibition of creatinine excretion rather than a decline in true GFR.
Clinical Bottom Line
Disappointingly, cobicistat did not appear to be significantly more tolerable than ritonavir, but it still will offer (if approved by the FDA) a needed alternative to ritonavir as a PK booster for PIs. The FDA recently approved the fixed-dose combination of elvitegravir/cobicistat/tenofovir/emtricitabine, and is considering approval of cobicistat as a stand-alone agent. It also is being studied in combination with darunavir, and in several novel coformulations.
As with ritonavir, cobicistat will have significant interactions with numerous other drugs; further research will be needed to clarify these interactions. Additionally, the creatinine elevations caused by cobicistat may be difficult to evaluate in the clinical setting, where we have a high level of concern for any signs of renal toxicity (especially with regimens that also contain tenofovir or other renally problematic drugs) and cannot measure true GFR.
- Gallant J, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as pharmacoenhancers in combination with atazanavir plus tenofovir disoproxil fumarate/emtricitabine: phase 3 randomized, double blind, active-controlled trial, week 48 results. In: Program and abstracts of the XIX International AIDS Society Conference; July 22-27, 2012; Washington, DC. Abstract TUAB0103.
Susa Coffey is medical editor of the NCRC. She is a Professor of Medicine at UCSF in the Division of HIV, Infectious Diseases and Global Medicine and a longtime clinician and educator in the HIV at San Francisco General Hospital clinic (“Ward 86”). She also is medical editor of HIV InSite.