Drug Interactions between copanlisib 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 copanlisib. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of copanlisib by certain compounds present in grapefruit. When a single 60 mg intravenous dose of copanlisib was administered to cancer patients in combination with the potent CYP450 3A4 and P-gp inhibitor, itraconazole (200 mg once daily for 10 days), mean copanlisib peak plasma concentration (Cmax) did not change but systemic exposure (AUC) increased by 53%. 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 copanlisib may increase the risk of adverse effects such as nausea, vomiting, diarrhea, stomatitis, hyperglycemia, hypertension, noninfectious pneumonitis, cutaneous reactions (e.g., exfoliative dermatitis, maculopapular rash), anemia, neutropenia, thrombocytopenia, and infections.

MANAGEMENT: Patients should avoid the consumption of grapefruit and grapefruit juice during treatment with copanlisib.