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Drug Interactions between adagrasib and mibefradil

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

mibefradil adagrasib

Applies to: mibefradil and adagrasib

ADJUST DOSING INTERVAL: Adagrasib can cause concentration-dependent, prolongation of the QT interval. Coadministration of potent CYP450 3A4 inhibitors before adagrasib has reached steady-state may significantly increase the plasma concentrations of adagrasib, which is primarily metabolized by the isoenzyme. From clinical studies, adagrasib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.4-fold and 4-fold, respectively, following concomitant use of a single dose of adagrasib (200 mg) with itraconazole, a potent CYP450 3A4 inhibitor. No clinically significant differences in the pharmacokinetics of adagrasib at steady state were predicted when used concomitantly with itraconazole. Elevated plasma concentrations of adagrasib may increase the risk for adverse effects such as QT prolongation, diarrhea, fatigue, musculoskeletal pain, hepatotoxicity, and renal impairment. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Adagrasib manufacturer recommends avoiding its concomitant use with potent CYP450 3A4 inhibitors 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.

References

  1. (2022) "Product Information. Krazati (adagrasib)." Mirati Therapeutics, Inc.

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Drug and food interactions

Major

adagrasib food

Applies to: adagrasib

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.

References

  1. (2022) "Product Information. Krazati (adagrasib)." Mirati Therapeutics, Inc.

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

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