Drug Interactions between Evotaz and fosamprenavir

MONITOR: Coadministration with fosamprenavir may decrease the plasma concentrations of atazanavir, even in the presence of low-dose ritonavir as a pharmacokinetic booster. The mechanism has not been described. In 22 study subjects, administration of atazanavir (300 mg once a day) with fosamprenavir/ritonavir (700 mg/100 mg twice a day) for 10 days decreased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atazanavir by 24% and 22%, respectively, compared to administration of atazanavir with ritonavir alone (300 mg/100 mg once a day) for 10 days. The clinical significance of these changes is unknown. In a study consisting of patients who have been intolerant to or have failed lopinavir/ritonavir, 14 patients who received atazanavir/fosamprenavir/ritonavir (150 or 200 mg/700 mg/100 mg twice a day, with or without nucleoside reverse transcriptase inhibitors) for 24 weeks all demonstrated plasma trough concentrations of atazanavir and amprenavir well above the minimum acceptable concentrations. In addition, the patients tolerated the regimen and had good antiretroviral response. At 24 weeks, 10 patients (60%) achieved HIV RNA levels below 400 copies/mL, and four had less than 50 copies/mL. Four patients required concomitant statins because of hyperlipidemia, which is a known side effect of protease inhibitors, in particular ritonavir. One patient developed grade 3 hyperlipidemia at week 8 and discontinued ritonavir with improvement. Three patients who did not tolerate ritonavir were switched to atazanavir/fosamprenavir (400 mg/700 mg twice a day), which also yielded good tolerance and antiretroviral response. Atazanavir reportedly does not significantly affect the pharmacokinetics of amprenavir from fosamprenavir.

MANAGEMENT: Appropriate dosages of atazanavir, fosamprenavir, and ritonavir with respect to safety and efficacy have not been established when used in combination. Limited data suggest that an atazanavir dosage of 150 or 200 mg twice daily may be adequate in combination with fosamprenavir 700 mg and ritonavir 100 mg twice daily. Therapeutic drug monitoring is recommended if this regimen is used, and antiretroviral response should be monitored closely.

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.