Drug Interactions between cobicistat / elvitegravir / emtricitabine / tenofovir disoproxil and oliceridine

MONITOR CLOSELY: Coadministration with moderate or potent inhibitors of CYP450 2D6 and/or 3A4 may increase the plasma concentrations and adverse opioid effects of oliceridine, which is primarily metabolized by both isoenzymes in vitro. In addition, oliceridine concentrations may decrease following discontinuation of a concomitant moderate or potent CYP450 2D6 or 3A4 inhibitor, possibly resulting in decreased opioid efficacy or withdrawal syndrome. The effect of a CYP450 2D6 inhibitor on the pharmacokinetics of oliceridine has not been studied. However, it may be similar to that reported in CYP450 2D6 poor metabolizers, whose plasma clearance of oliceridine is reduced by approximately 50% compared to those who are nonpoor CYP450 2D6 metabolizers. The clearance may be further reduced with the addition of a CYP450 3A4 inhibitor. When a single 0.25 mg dose of oliceridine was given to poor metabolizers of CYP450 2D6 following pretreatment with the potent CYP450 3A4 inhibitor itraconazole (200 mg once daily for 5 days), oliceridine systemic exposure (AUC) increased by approximately 80% while peak plasma concentration (Cmax) was not significantly affected. Furthermore, mean oliceridine clearance decreased to approximately 30% of that observed in nonpoor metabolizers of CYP450 2D6. The interaction has not been studied with other, less potent CYP450 3A4 inhibitors.

MANAGEMENT: Caution is recommended if oliceridine is used in combination with moderate or potent inhibitors of CYP450 2D6 or 3A4. If concomitant use is considered necessary, patients may require less frequent dosing of oliceridine and should be closely monitored for respiratory depression, sedation, and QT prolongation. If a moderate or potent CYP450 2D6 or 3A4 inhibitor is discontinued, an increase of the oliceridine dosage may be considered while monitoring for signs of opioid withdrawal until stable drug effects are achieved. Due to the prolonged duration of CYP450 2D6 inhibition by the moderate CYP450 2D6 inhibitor rolapitant, prolonged monitoring for adverse effects of oliceridine for at least 28 days after administration of rolapitant may be required.

MONITOR: Concomitant use of tenofovir with cobicistat may increase the risk for tenofovir-related renal adverse effects, including renal impairment, renal failure, elevated creatinine, and Fanconi syndrome. The mechanism of this interaction has not been described. Cobicistat may decrease estimated creatinine clearance via inhibition of tubular secretion of creatinine; however, renal glomerular function does not appear to be affected. When given concomitantly with cobicistat, the systemic exposure (AUC) and trough plasma concentrations (Cmin) of tenofovir was also increased by 23% and 55%, respectively. However, data are lacking to determine whether concomitant use of tenofovir with cobicistat-containing regimens is associated with a greater risk of renal complications compared with regimens that do not include cobicistat.

MANAGEMENT: Initiation of cobicistat or cobicistat-containing regimens is not recommended in patients with CrCl less than 70 mL/min if any coadministered medicine requires dose adjustment based on renal function (including tenofovir), or is nephrotoxic. If concomitant therapy is necessary, monitoring of renal function is recommended, particularly in patients with risk factors for renal impairment.

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.