Drug Interactions between lorlatinib and lurasidone

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of lurasidone. 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. When a single 10 mg dose of lurasidone was administered with the potent CYP450 3A4 inhibitor ketoconazole (400 mg/day for 5 days), lurasidone peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 6.9- and 9.0-fold, respectively, compared to administration alone. The AUC of lurasidone's active metabolite increased by 6-fold. Another potent CYP450 3A4 inhibitor, posaconazole, has been reported to increase lurasidone AUC by approximately 4.5-fold. When a single 20 mg dose of lurasidone was administered with the moderate CYP450 3A4 inhibitor diltiazem (extended release formulation 240 mg/day for 5 days), lurasidone Cmax and AUC increased by 2.1- and 2.2-fold, respectively, while the AUC of the active metabolite increased by 2.4-fold. 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.

GENERALLY AVOID: Alcohol may potentiate some of the central nervous system and hypotensive effects of lurasidone. Use in combination may result in increased sedation, dizziness, hypotension, and impairment of judgment, thinking, and psychomotor skills.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of lurasidone. According to the product labeling, lurasidone mean Cmax and AUC were increased approximately 3-fold and 2-fold, respectively, when administered with food relative to under fasting conditions. Lurasidone AUC was not affected by meal size (in the range of 350 to 1000 calories) or fat content. In clinical studies, lurasidone was administered with food.

MANAGEMENT: Patients treated with lurasidone should avoid consumption of grapefruit and grapefruit juice as well as alcohol. Lurasidone should be taken with food (at least 350 calories).

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.