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

CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of venetoclax, which is primarily metabolized by the isoenzyme. In a study of 11 previously treated non-Hodgkin lymphoma patients, when the potent CYP450 3A4 inhibitor, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor ketoconazole (400 mg daily for 7 days) was coadministered with venetoclax (50 mg single dose), venetoclax peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.3-fold and 6.4-fold, respectively. Likewise, concomitant use of the P-gp and potent CYP450 3A4 inhibitor posaconazole (300 mg) with venetoclax 50 mg or 100 mg daily for 7 days increased the venetoclax Cmax by 1.61-fold and 1.86-fold, respectively, and AUC by 1.9-fold and 2.44-fold, respectively, compared with venetoclax (400 mg daily) alone. Increased venetoclax exposure may potentiate the risk of tumor lysis syndrome, particularly at initiation of therapy and during the dosage ramp-up phase, as well as other adverse effects such as diarrhea, nausea, vomiting, neutropenia, anemia, and thrombocytopenia.

MANAGEMENT: In patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), the concomitant use of potent CYP450 3A4 inhibitors is contraindicated during the initiation and dosage ramp-up phase of venetoclax. The manufacturer also advises against use of potent CYP450 3A4 inhibitors once the dosage ramp-up phase is completed and the steady daily dose phase of venetoclax therapy begins. However, if concomitant therapy with a potent CYP450 3A4 inhibitor other than posaconazole is considered necessary, the daily dose of venetoclax should be reduced to 100 mg or less. If a dose had already been modified for venetoclax-related adverse reactions/toxicities in accordance with product labeling, some authorities suggest the dose should be further reduced by 75%. If concomitant use with posaconazole is required during the steady daily dose phase of therapy, the manufacturer advises the venetoclax dosage be reduced to 70 mg.

In patients with acute myeloid leukemia (AML), the dose of venetoclax should be reduced when coadministered with potent CYP450 3A4 inhibitors. This adjustment applies throughout both the initiation and dosage ramp-up phases, as well as the ongoing steady daily dose phase of therapy. During the initiation and ramp-up phases, the recommended schedule from the manufacturer is 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, and 100 mg on day 4. Following completion of the ramp-up phase, a maintenance dose of 100 mg or less per day is advised for the steady daily dose phase. Some authorities suggest reducing the dose by at least 75% if adjustments have already been made due to venetoclax-related adverse reactions or toxicities. However, in cases where concurrent use with posaconazole is necessary, certain authorities propose a similar initiation and ramp-up phase dosing regimen of venetoclax from days 1 to 3 , followed by 70 mg on day 4, and continuing into the steady daily dose phase of therapy.

All patients, regardless of indication, should be closely monitored for signs and symptoms of venetoclax-induced adverse effects/toxicities. In addition, the dosage used prior to initiating the potent CYP450 3A4 inhibitor may be resumed 2 to 3 days after discontinuation of the inhibitor.

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.