Drug Interactions between adagrasib and Lanoxin

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.

Administration of digoxin with a high-fiber meal has been shown to decrease its bioavailability by almost 20%. Fiber can sequester up to 45% of the drug when given orally. Patients should be advised to maintain a regular diet without significant fluctuation in fiber intake while digoxin is being titrated.

Grapefruit juice may modestly increase the plasma concentrations of digoxin. The mechanism is increased absorption of digoxin due to mild inhibition of intestinal P-glycoprotein by certain compounds present in grapefruits. In 12 healthy volunteers, administration of grapefruit juice with and 30 minutes before, as well as 3.5, 7.5, and 11.5 hours after a single digoxin dose (0.5 mg) increased the mean area under the plasma concentration-time curve (AUC) of digoxin by just 9% compared to administration with water. Moreover, P-glycoprotein genetic polymorphism does not appear to influence the magnitude of the effects of grapefruit juice on digoxin. Thus, the interaction is unlikely to be of clinical significance.