Drug Interaction Report

GENERALLY AVOID: Coadministration of lorlatinib with drugs that are P-glycoprotein (P-gp) substrates may decrease the plasma concentration and pharmacologic effect of the P-gp substrate. The proposed mechanism is induction of P-gp mediated drug efflux by lorlatinib. When a single 60 mg oral dose of fexofenadine (a P-gp substrate) was administered with lorlatinib (100 mg orally once daily for 15 days), fexofenadine peak plasma concentration (Cmax) decreased by 63% and systemic exposure (AUC) decreased by 67% indicating that lorlatinib is a moderate inducer of P-gp.

MANAGEMENT: Concomitant use of lorlatinib with drugs that are P-gp substrates should generally be avoided, especially those P-gp substrates for which minimal concentration changes may lead to serious therapeutic failures. If coadministration is required, consider dosage adjustments and clinical and laboratory monitoring whenever lorlatinib is added to or withdrawn from therapy. P-gp substrate dosage may need to be increased in accordance with approved product labeling.

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.