Drug Interactions between adagrasib and Toviaz

ADJUST DOSING INTERVAL: Adagrasib can cause concentration-dependent, prolongation of the QT interval. Theoretically, coadministration with grapefruit juice before adagrasib has reached steady-state may significantly increase the plasma concentrations of adagrasib, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been reported for the potent CYP450 3A4 inhibitor, itraconazole. In a clinical drug interaction study, adagrasib peak plasma concentration (Cmax) and systemic exposure (AUC) were increased by 2.4-fold and 4-fold, respectively following concomitant use of a single dose of adagrasib (200 mg) with itraconazole. No clinically significant differences in the pharmacokinetics of adagrasib at steady state were predicted when used concomitantly with itraconazole. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to adagrasib may increase the risk of adverse effects such as QT prolongation, diarrhea, fatigue, musculoskeletal pain, hepatotoxicity, and renal impairment.

Adagrasib pharmacokinetics were not significantly affected when administered with a high-fat meal.

MANAGEMENT: Although clinical data are lacking, it may be advisable to avoid the consumption of grapefruit or grapefruit juice until adagrasib concentrations have reached steady state (after approximately 8 days). 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. Adagrasib may be administered with or without food.

MONITOR: Coadministration with moderate inhibitors of CYP450 3A4 such as grapefruit juice may increase the plasma concentrations of fesoterodine's active metabolite, 5-hydroxymethyl tolterodine, which is partially metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of fesoterodine should be considered. Because 5-hydroxymethyl tolterodine is also metabolized by CYP450 2D6, the clinical significance of the interaction may be greater in patients who are CYP450 2D6-deficient, or so-called poor metabolizers of CYP450 2D6 (approximately 7% of Caucasians and less than 2% of Asians and individuals of African descent) who may rely more on the 3A4 metabolic pathway for clearance of the drug.

MANAGEMENT: Caution is advised if fesoterodine is administered with grapefruit or grapefruit juice. Patients should be advised to notify their physician if they experience potential adverse effects of fesoterodine such as irregular heartbeat, blurry vision, difficulty urinating, dry mouth, headache, drowsiness, dizziness, gastrointestinal upset, or constipation.