Drug Interaction Report

MONITOR: Coadministration with osilodrostat may increase the plasma concentrations of drugs that are metabolized by CYP450 1A2, 2C19, 2D6, and/or 3A4. Osilodrostat has been shown to be a moderate inhibitor of CYP450 1A2, a mild to borderline moderate inhibitor of CYP450 2C19, and a weak inhibitor of CYP450 2D6 and 3A4. In a pharmacokinetic study with 20 healthy volunteers using a single 50 mg dose of osilodrostat and a probe drug cocktail, osilodrostat increased the exposures to caffeine (CYP450 1A2 substrate), omeprazole (CYP450 2C19 substrate), dextromethorphan (CYP450 2D6 substrate), and midazolam (CYP450 3A4/5 substrate) by 2.5-, 1.9-, 1.5- and 1.5-fold, respectively.

MANAGEMENT: Caution is advised when osilodrostat is used concurrently with drugs that are substrates of CYP450 1A2, 2C19, 2D6 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever osilodrostat is added to or withdrawn from therapy.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of naldemedine. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In pharmacokinetic studies, naldemedine systemic exposure (AUC) was increased approximately 90% by the moderate CYP450 3A4 inhibitor fluconazole and nearly 200% by the potent inhibitor itraconazole. The interaction has not been studied with grapefruit juice. 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 naldemedine may precipitate opioid withdrawal symptoms such as hyperhidrosis, lacrimation, rhinorrhea, chills, diarrhea, abdominal pain, anxiety, insomnia, irritability, restlessness, and yawning.

Food does not significantly affect the overall bioavailability of naldemedine. When administered with a high-fat meal, the rate of naldemedine absorption was decreased, but not the extent. Specifically, naldemedine peak plasma concentration (Cmax) was decreased by approximately 35% and time to achieve Cmax was delayed from 0.75 hours in the fasted state to 2.5 hours in the fed state, while naldemedine AUC was not significantly changed.

MANAGEMENT: Naldemedine may be taken with or without food. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with naldemedine.