Drug Interactions between cobicistat / darunavir and saquinavir

GENERALLY AVOID: Coadministration with saquinavir may decrease the plasma concentrations of darunavir, even in the presence of low-dose ritonavir as a pharmacokinetic booster. The mechanism of interaction has not been described. In 14 study subjects, administration of darunavir/ritonavir (400 mg/100 mg twice a day) with saquinavir (hard gel capsule 1000 mg twice a day) decreased the peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and trough plasma concentration (Cmin) of darunavir by 17%, 26% and 42%, respectively, compared to administration without saquinavir. No statistically significant changes were reported for saquinavir Cmax, AUC, and Cmin during coadministration with darunavir/ritonavir compared to administration of saquinavir with ritonavir alone (1000 mg/100 mg twice a day).

MANAGEMENT: The appropriate dosage of darunavir when prescribed in combination with saquinavir has not been established. Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, the use of darunavir with saquinavir is not recommended, with or without low-dose ritonavir.

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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.

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