Drug Interactions between Krazati and lomitapide

ADJUST DOSING INTERVAL: Administration of lomitapide with food may increase the risk of common gastrointestinal adverse reactions such as diarrhea, nausea, vomiting, dyspepsia, abdominal pain or discomfort, abdominal distension, constipation, and flatulence. Absorption of concomitant oral medications may be affected in patients who develop diarrhea or vomiting.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of lomitapide. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Weak CYP450 3A4 inhibitors can increase lomitapide exposure (AUC) by approximately 2-fold according to the product labeling. Ketoconazole, a potent CYP450 3A4 inhibitor, has been shown to increase lomitapide AUC by 27-fold .

GENERALLY AVOID: Coadministration with alcohol may increase the risk of hepatotoxicity associated with the use of lomitapide. In a premarketing clinical trial, 34% (10/29) of patients treated with lomitapide had at least one elevation in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 3 times the upper limit of normal (ULN) or greater, and 14% (4/29) had at least one elevation in ALT or AST 5 times ULN or greater. There were no concomitant clinically meaningful elevations of total bilirubin, international normalized ratio (INR), or alkaline phosphatase. Lomitapide also increases hepatic fat, with or without concomitant increases in transaminases. In the same study, the median absolute increase in hepatic fat was 6% after both 26 and 78 weeks of treatment, from 1% at baseline, measured by magnetic resonance spectroscopy. Hepatic steatosis associated with lomitapide may be a risk factor for progressive liver disease, including steatohepatitis and cirrhosis. Clinical data suggest that hepatic fat accumulation is reversible after stopping treatment with lomitapide, although the long-term consequences are unknown.

MANAGEMENT: Lomitapide should be taken once daily with a glass of water, without food, at least 2 hours after the evening meal. Strict adherence to a low-fat diet (<20% of total calories from fat) and gradual dosage titration may also help to reduce gastrointestinal intolerance. Patients should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract during treatment with lomitapide. Since alcohol may increase levels of hepatic fat and induce or exacerbate liver injury, the manufacturer recommends that patients taking lomitapide not consume more than one alcoholic drink per day.

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.