Drug Interactions between abemaciclib and lorlatinib

GENERALLY AVOID: Grapefruit and grapefruit juice may significantly increase the plasma concentrations of lorlatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients treated with lorlatinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. If coadministration is unavoidable, some authorities recommend reducing the initial dosage of lorlatinib from 100 mg orally once daily to 75 mg orally once daily. In patients who have had a dosage reduction to 75 mg orally once daily due to adverse reactions, the lorlatinib dosage should be further reduced to 50 mg orally once daily upon initiation of a potent CYP450 3A4 inhibitor. After 3 plasma half-lives following discontinuation of the potent CYP450 3A4 inhibitor, the lorlatinib dosage may be increased to that used prior to initiation of the inhibitor.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of abemaciclib. 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 other CYP450 3A4 inhibitors. According to the product labeling, abemaciclib systemic exposure (AUC) is predicted to increase by up to 16-fold when administered with the potent CYP450 3A4 inhibitor ketoconazole. Itraconazole, another potent inhibitor, is predicted to increase the relative potency-adjusted unbound AUC of abemaciclib plus its active metabolites by 2.2-fold. In cancer patients, administration of a single 50 mg dose of abemaciclib (one-third the approved recommended dose of 150 mg) with clarithromycin 500 mg twice daily increased the relative potency-adjusted unbound AUC of abemaciclib plus its active metabolites by 2.5-fold relative to abemaciclib administered alone. The moderate CYP450 3A4 inhibitors, diltiazem and verapamil, are predicted to increase the relative potency-adjusted unbound AUC of abemaciclib plus its active metabolites by 2.4-fold and 1.6-fold, respectively. 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 abemaciclib may increase adverse effects such as nausea, vomiting, diarrhea, stomatitis, venous thromboembolism, hepatotoxicity, anemia, neutropenia, and thrombocytopenia.

Food has modest effects on the pharmacokinetics of abemaciclib. A high-fat, high-calorie meal (800 to 1000 calories; 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) administered to healthy subjects increased the Cmax and AUC of abemaciclib plus its active metabolites by 26% and 9%, respectively.

MANAGEMENT: Abemaciclib may be administered with or without food. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with abemaciclib.