Drug Interactions between atazanavir / cobicistat and etravirine

GENERALLY AVOID: Coadministration with etravirine may decrease the plasma concentrations of atazanavir, with or without cobicistat or low-dose ritonavir as a pharmacokinetic booster. The plasma concentrations of cobicistat may also be reduced. The mechanism is etravirine induction of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of atazanavir, other protease inhibitors, and cobicistat. In 14 study subjects administered atazanavir 400 mg once a day with etravirine, atazanavir trough plasma concentration (Cmin) decreased significantly by approximately 47%. In 20 HIV-infected patients administered atazanavir-ritonavir (300 mg/100 mg) once a day with etravirine, the atazanavir Cmin decreased by 18%; this reduction is not considered clinically relevant. In contrast, etravirine plasma concentration is increased by the protease inhibitors, presumably due to inhibition of CYP450 3A4. Both etravirine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 50% during coadministration with atazanavir and 30% during coadministration with atazanavir-ritonavir, while etravirine Cmin increased by 58% and 26%, respectively. The systemic exposure of etravirine during coadministration with atazanavir-ritonavir was similar to exposures of etravirine observed during Phase 3 trials, where all subjects received darunavir-ritonavir as part of the background regimen.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, neither unboosted atazanavir nor atazanavir boosted with cobicistat should be prescribed in combination with etravirine. According to the product labeling for etravirine, atazanavir boosted with ritonavir may be given concomitantly with etravirine in treatment-experienced patients without dose adjustments.

GENERALLY AVOID: Cobicistat may increase the plasma concentrations of antiretroviral agents. The plasma concentrations of cobicistat may also be increased or reduced in the presence of antiretroviral agents. The proposed mechanism is cobicistat inhibition of the CYP450 3A4 isoenzyme, of which antiretroviral agents may be substrates, and the inhibition or induction of CYP450 3A4 by concomitant antiretroviral medications. Cobicistat is a mechanism-based inhibitor and substrate of CYP450 3A4 with no antiretroviral activity of its own. Rather, it is indicated in its capacity as a pharmacokinetic booster of CYP450 3A4 to increase the systemic exposure of some antiretroviral medications such as atazanavir, darunavir, and elvitegravir, which are substrates of this isoenzyme. Concomitant use of other antiretroviral agents with cobicistat may also increase the plasma levels and risk of side effects associated with these medicines. In contrast, concomitant use of cobicistat-boosted atazanavir or darunavir with CYP450 3A4 inducers nevirapine, etravirine, or efavirenz may reduce the plasma concentrations of cobicistat, darunavir, and atazanavir, leading to a potential loss of therapeutic effect and development of resistance to darunavir and atazanavir. Pharmacokinetic data are not available.

MANAGEMENT: Cobicistat is not intended for use with more than one antiretroviral medication that requires pharmacokinetic enhancement, such as two protease inhibitors or elvitegravir in combination with a protease inhibitor. In addition, cobicistat should not be used concomitantly with ritonavir due to their similar effects on CYP450 3A4. According to some authorities, use of the antiretroviral combinations of atazanavir-cobicistat or darunavir-cobicistat concomitantly with the CYP450 3A4 inducers efavirenz, etravirine, or nevirapine is also not recommended. Other authorities consider the administration of atazanavir-cobicistat with efavirenz or nevirapine to be contraindicated. Since dosing recommendations have only been established for a number of antiretroviral medications, product labeling and current antiretroviral treatment guidelines should be consulted.