Drug Interactions between larotrectinib and solifenacin

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of solifenacin, which is primarily metabolized by the isoenzyme. According to the product labeling, administration of solifenacin (10 mg) in combination with the potent CYP450 3A4 inhibitor ketoconazole (400 mg) increased solifenacin mean peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.5- and 2.7-fold, respectively, compared to administration alone. The interaction has not been studied with less potent CYP450 3A4 inhibitors. Solifenacin is associated with dose-related prolongation of the QT interval. A nearly threefold increase in AUC as observed when given with ketoconazole would be approximately equivalent to administration of a 30 mg dose, whose effect on the QT interval has been studied in a multidose, randomized, double-blind, placebo and positive-controlled (moxifloxacin 400 mg) study of 76 female volunteers aged 19 to 79 years. For the 10 mg and 30 mg doses, mean changes in Fridericia-corrected QT interval (QTcF) from baseline at the time of peak plasma concentration (Tmax) were 2 and 8 msec, respectively, relative to placebo. These changes are less than those observed with moxifloxacin 400 mg, whose placebo-subtracted mean changes in QTcF from baseline ranged from 11 to 16 msec in three sessions. However, the confidence intervals overlapped, and the study was not designed to draw direct statistical conclusions between the drugs or the dose levels.

MANAGEMENT: Pharmacologic response to solifenacin should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the solifenacin dosage adjusted if necessary. Patients should be advised to contact their physician if they experience undue adverse effects of solifenacin such as severe abdominal pain or constipation for 3 or more days. Patients should seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, shortness of breath, or syncope.