Drug Interactions between lorlatinib and Mycapssa

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.

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MONITOR: Due to their gastrointestinal pharmacologic effects, somatostatin analogs (e.g., octreotide, lanreotide) may variously affect the absorption of dietary nutrients and concomitantly administered oral medications. Somatostatin analogs have been shown to prolong gastrointestinal transit time and inhibit intestinal absorption of some nutrients such as fat. Clinical data are limited, however. In case reports, octreotide has been reported to reduce the relative bioavailability of cyclosporine. Transplant rejection and significant reductions in cyclosporine levels, sometimes to undetectable levels, have been reported in association with the interaction. Vitamin K absorption was not affected when concomitantly administered with lanreotide according to the manufacturer.

MANAGEMENT: Clinicians should be aware of the potential for altered absorption of concomitantly administered oral medications during treatment with somatostatin analogs. Blood levels and clinical response should be monitored, particularly for drugs that have a narrow therapeutic index, and the dosages adjusted as necessary.

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