Drug Interactions between entrectinib and lopinavir / ritonavir

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of entrectinib, which is primarily metabolized by the isoenzyme. When a single 100 mg dose of entrectinib was administered with itraconazole, a potent CYP450 3A4 inhibitor, entrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.7- and 6-fold, respectively. Increased exposure to entrectinib may increase the risk and/or severity of adverse effects such as cognitive impairment, mood disorders, dizziness, sleep disturbances, liver enzyme elevations, hyperuricemia, congestive heart failure, edema, myocarditis, QT prolongation, vision problems, anemia, and neutropenia.

MANAGEMENT: Concomitant use of entrectinib with potent CYP450 3A4 inhibitors should be avoided when possible. If coadministration is necessary, the dosage of entrectinib should be reduced to 100 mg once daily for adults and pediatrics patients (12 years and older) with a body surface area (BSA) greater than 1.5 m2. Following discontinuation, and after an appropriate washout period of the CYP450 3A4 inhibitor (i.e., 3 to 5 half-lives), the entrectinib dosage taken prior to initiating the CYP450 3A4 inhibitor may be resumed. For pediatric patients with a body surface area of 1.5 m2 or less, concomitant use of entrectinib with potent CYP450 3A4 inhibitors should be avoided. Some authorities recommend if coadministration is unavoidable, adult patients should follow dose reduction guidance as described above while limiting coadministration to 14 days and do not recommend coadministration in pediatric patients (UK).

GENERALLY AVOID: Entrectinib may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. Of 355 patients who received entrectinib in clinical trials at dosages ranging from 100 mg to 2600 mg daily (75% received 600 mg orally once daily), 3.1% of patients with at least one post-baseline QTc measurement experienced QTcF interval prolongation of >60 msec and 0.6% had a QTcF interval >500 msec. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of entrectinib with other drugs that can prolong the QT interval should generally be avoided. Caution and clinical monitoring are recommended if concomitant use is required. Patients should have electrocardiograms (ECGs) performed prior to initiation of entrectinib, after 1 month of treatment with entrectinib, and periodically during treatment as appropriate based on individual risk factors. Some authorities suggest that if the QTc interval is between 481 to 500 msec at any time during treatment, entrectinib should be withheld until QTc is recovered to baseline at which time treatment at the same dose may be resumed (AU, UK). If the QTc is greater than 500 msec, entrectinib should be withheld until the QTc interval recovers to baseline at which time the same dose may be resumed if factors that caused the QT prolongation are corrected. However, if these factors are not identified and corrected, entrectinib should be resumed at a reduced dose. Entrectinib should be permanently discontinued in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia such as torsade de pointes or polymorphic ventricular tachycardia. Because hypokalemia and hypomagnesemia are risk factors for ventricular arrhythmias, electrolyte levels should also be obtained prior to and during treatment, and any abnormalities corrected as necessary. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.