Drug Interactions between atazanavir / cobicistat and Viekira XR

ADJUST DOSE: Coadministration of atazanavir plus ritonavir in combination with ombitasvir/paritaprevir/ritonavir plus dasabuvir may significantly increase the plasma concentrations of paritaprevir. The mechanism may involve inhibition of both CYP450 3A4-mediated metabolism and P-glycoprotein-mediated transport by atazanavir and ritonavir. In 12 study subjects, administration of once daily morning doses of ombitasvir/paritaprevir/ritonavir (25 mg/150 mg/100 mg) plus twice daily doses of dasabuvir concomitantly with atazanavir 300 mg plus ritonavir 100 mg once daily in the evening (12 hours after morning doses of ombitasvir/paritaprevir/ritonavir plus dasabuvir) resulted in increases of approximately 2.2-, 3.2- and 12-fold in mean paritaprevir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin), respectively. Mean ritonavir Cmax, AUC and Cmin also increased by approximately 1.6-, 3.2- and 24.7-fold, respectively, presumably due to dose-related increases from the additional dose of ritonavir per day. The mean Cmax and AUC of ombitasvir and dasabuvir were reduced slightly, by less than 20%, while the AUC and Cmin of atazanavir were increased by 19% and 68%, respectively.

MONITOR CLOSELY: Coadministration of atazanavir with ombitasvir/paritaprevir/ritonavir plus dasabuvir may increase the risk of hyperbilirubinemia. Both atazanavir and paritaprevir can cause elevations in indirect (unconjugated) bilirubin, the former by inhibition of UGT1A1 and the latter by inhibition of OATP1B1/1B3. In 63 subjects with HCV/HIV-1 coinfection, elevations in total bilirubin (mostly indirect) greater than two times the upper limit of normal occurred in 34 (54%) of subjects receiving ombitasvir/paritaprevir/ritonavir plus dasabuvir with ribavirin, 15 of whom were also receiving atazanavir at the time of bilirubin elevation. Nine of these patients also had adverse events of ocular icterus, jaundice, or hyperbilirubinemia. None of the subjects with hyperbilirubinemia had concomitant elevations of aminotransferases.

MANAGEMENT: When coadministered with ombitasvir/paritaprevir/ritonavir plus dasabuvir, atazanavir 300 mg should be given in the morning without ritonavir. The ritonavir component of the HIV antiretroviral regimen should be restarted after completion of treatment with ombitasvir/paritaprevir/ritonavir plus dasabuvir.

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ADJUST DOSE: Coadministration with ritonavir may significantly increase the plasma concentrations of atazanavir. The mechanism is ritonavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of atazanavir. In 28 study subjects, ritonavir (100 mg once a day for 10 days) increased the mean steady-state peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and trough plasma concentration (Cmin) of atazanavir (300 mg once a day) by 86%, 238% and over 1000%, respectively, compared to administration of atazanavir alone. Compared with historical data from standard therapeutic dosing of atazanavir alone at 400 mg once a day, administration of atazanavir/ritonavir at 300 mg/100 mg once a day increased atazanavir mean Cmax, AUC and Cmin by 18%, 103% and 671%, respectively.

MANAGEMENT: Patients requiring the combination should be prescribed atazanavir 300 mg with ritonavir 100 mg as a single daily dose with food.

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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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MONITOR: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of paritaprevir, which is primarily metabolized by the isoenzyme. In 12 study subjects, ketoconazole 400 mg given once daily increased single-dose paritaprevir peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 37% and 98%, respectively. The risk of hyperbilirubinemia may be increased, as paritaprevir can cause elevations in indirect (unconjugated) bilirubin via inhibition of OATP1B1/1B3.

MANAGEMENT: Caution is advised if paritaprevir is prescribed in combination with potent CYP450 3A4 inhibitors. Patients should be monitored for signs and symptoms of hepatotoxicity (i.e., ALT and bilirubin elevations).

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