Drug Interactions between adagrasib and etrasimod

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.

GENERALLY AVOID: Coadministration with moderate inhibitors of CYP450 3A4 such as grapefruit juice in patients who known or suspected to be poor CYP450 2C9 metabolizers may increase the exposure of etrasimod. Etrasimod is primarily metabolized by the isoenzymes CYP450 3A4, 2C8, and 2C9. Pharmacokinetic studies have reported that no single enzyme system appears to dominate the elimination pathway of etrasimod. Therefore, the involvement of multiple CYP450 isoforms reduces the likelihood of drug-drug interactions when only a single CYP450 isoform is strongly or moderately inhibited by a coadministered drug. In clinical drug interaction studies, when etrasimod was administered with the dual moderate CYP450 2C9 and 3A4 inhibitor fluconazole at steady-state levels, etrasimod systemic exposure (AUC) increased by 84%. However, concomitant use with the potent CYP450 3A4 inhibitor itraconazole increased the AUC of etrasimod by 32%, which was not considered by the manufacturer to be clinically significant. The effect on etrasimod systemic exposure in CYP450 2C9 intermediate metabolizers treated with less potent CYP450 3A4 inhibitors is not known. Increased plasma concentrations of etrasimod may increase the risk of infection, bradyarrhythmia, AV conduction delays, elevated transaminase levels, and macular edema.

MANAGEMENT: Until further information is available, the consumption of grapefruit and grapefruit juice in combination with moderate to potent CYP450 2C8 inhibitors such as gemfibrozil should be avoided or limited during treatment with etrasimod in patients who are poor CYP450 2C9 metabolizers. Caution is recommended with grapefruit products consumption in patients who are intermediate CYP450 2C9 metabolizers. Patients should be advised to notify their physician if they experience potential adverse effects of etrasimod.