Drug Interactions between emtricitabine / lopinavir / ritonavir / tenofovir disoproxil and encorafenib

GENERALLY AVOID: Coadministration of encorafenib with a drug that is both a substrate as well as a potent inhibitor of CYP450 3A4 may result in significantly increased plasma concentrations of encorafenib and significantly decreased plasma concentrations of the other drug. Encorafenib itself is a substrate and a potent inducer of CYP450 3A4. When a single 50 mg dose of encorafenib (equivalent to 0.1 times the recommended dose) was administered with posaconazole, a potent CYP450 3A4 inhibitor, encorafenib peak plasma concentration (Cmax) increased by 68% and systemic exposure (AUC) increased by 3-fold. Increased exposure to encorafenib may increase the risk of serious and life-threatening adverse effects such as hemorrhage, uveitis, QT prolongation, hepatotoxicity, dermatologic reactions, and new malignancies. Conversely, administration of a single 2 mg dose of the sensitive CYP450 3A4 substrate midazolam after repeated administration of encorafenib 450 mg once daily and binimetinib 45 mg twice daily resulted in decreased systemic exposure (AUC) and peak plasma concentration (Cmax) of midazolam by approximately 82% and 74%, respectively, compared to midazolam alone. Reduced plasma concentrations may potentially lead to decreased efficacy of the CYP450 3A4 substrate.

MANAGEMENT: Concomitant use of encorafenib with potent CYP450 3A4 inhibitors that are also sensitive CYP450 3A4 substrates should generally be avoided. If coadministration is required, the manufacturer recommends reducing the encorafenib dose to one-third of the dose used prior to addition of the potent CYP450 3A4 inhibitor. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, the encorafenib dose that was taken prior to initiating the inhibitor may be resumed. In addition, patients should be monitored for reduced efficacy of the concomitant medication. If the concomitant medication also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath. The prescribing information for any concomitant medication should also be consulted for further guidance and assessment of benefits versus risks of coadministration, as well as any dosage adjustments that may be required during coadministration and/or following the discontinuation of the potent CYP450 3A4 inhibitor.

MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

MONITOR: Coadministration with ritonavir, with or without lopinavir, has been suggested in postmarketing reports to increase the proximal tubular intracellular concentrations of tenofovir and potentiate the risk of tenofovir-induced nephrotoxicity. The proposed mechanism is ritonavir inhibition of tenofovir renal tubular secretion into the urine via multidrug resistance protein MRP2. Analysis of data from a compassionate access study in which 271 patients with advanced HIV disease received the combination for a mean duration of 63 weeks revealed no clinically significant nephrotoxicity associated with coadministration. However, there have been case reports of renal failure associated with acute tubular necrosis, Fanconi's syndrome, and nephrogenic diabetes insipidus in patients treated with tenofovir disoproxil fumarate in combination with ritonavir. Some patients had incomplete recovery of renal function more than a year after cessation of tenofovir therapy. Ritonavir given in combination with lopinavir has also been reported to modestly increase the plasma concentrations of tenofovir. In contrast, both slight decreases and no change in lopinavir and ritonavir concentrations have been reported.

MANAGEMENT: Caution is advised if tenofovir disoproxil fumarate is prescribed with ritonavir. Renal function should be monitored regularly, including surveillance for signs of tubulopathy such as glycosuria, acidosis, increases in serum creatinine level, electrolyte disturbances (e.g., hypokalemia, hypophosphatemia), and proteinuria. The same precaution may be applicable during therapy with other protease inhibitors based on their similar pharmacokinetic profile, although clinical data are lacking. Nelfinavir reportedly does not alter the pharmacokinetics of tenofovir, or vice versa. Tenofovir administration should be discontinued promptly if nephropathy develops.

MONITOR: Coadministration of lopinavir-ritonavir with inducers of CYP450 3A4 may decrease the plasma concentrations of lopinavir, which is primarily metabolized by the isoenzyme. Clinical studies have shown that potent CYP450 3A4 inducers such as rifampin and phenytoin can significantly alter the plasma concentrations of lopinavir, possibly by overriding some of the inhibiting effects of ritonavir and enhancing the clearance of both lopinavir and ritonavir. In 22 healthy, HIV-negative subjects, administration of lopinavir-ritonavir (400 mg-100 mg twice daily for 20 days) with rifampin (600 mg once daily for 10 days) decreased lopinavir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 55%, 75% and 99%, respectively. In another study of 12 healthy volunteers, coadministration of lopinavir-ritonavir (400 mg-100 mg twice daily for 22 days) and phenytoin (300 mg once daily on days 11 through 22) resulted in decreases in Cmax, AUC and Cmin of lopinavir by 24%, 33% and 46%, respectively. Ritonavir Cmax, AUC and Cmin were also reduced by 20%, 28% and 47%, respectively, although only the change in Cmin was statistically significant. The extent to which other, less potent inducers of CYP450 3A4 may interact with lopinavir-ritonavir is unknown. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can prolong the QT interval (e.g., apalutamide, encorafenib, enzalutamide) may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, caution is advised if lopinavir-ritonavir is prescribed with CYP450 3A4 inducers. Close clinical and laboratory monitoring of antiretroviral response is recommended. If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath. The prescribing information for the concomitant CYP450 3A4 inducers should be consulted for specific recommendations.

MONITOR: Coadministration with encorafenib may increase the plasma concentrations of drugs that are substrates of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic cation transporter (OCT2), organic anion transporter (OAT1, OAT3), organic anion transporting polypeptide (OATP1B1, OATP1B3), or uridine diphosphate glucuronosyltransferase (UGT) 1A1. In in vivo studies, encorafenib has been shown to be an inhibitor of OATP1B1, 1B3, and BCRP. In vitro studies have demonstrated it to be an inhibitor of OCT2, OAT1, OAT3, and P-gp at expected clinical concentrations as well as a potent, reversible inhibitor of UGT1A1. Administration of a single dose of rosuvastatin, an OATP1B1, OATP1B3 and BCRP substrate, after repeated administration of encorafenib 450 mg once daily and binimetinib 45 mg twice daily, resulted in increased systemic exposure (AUC) and peak plasma concentration (Cmax) of rosuvastatin by approximately 1.6 fold and 2.7 fold respectively.

MANAGEMENT: Caution is advised if encorafenib must be used concomitantly with drugs that are substrates of the affected transporters or UGT1A1, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever encorafenib is added to or withdrawn from therapy.