Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of lumateperone. In vitro studies show that multiple enzymes are involved in the metabolism of lumateperone, including but not limited to uridine 5'-diphospho-glucuronosyltransferases (UGT) 1A1, 1A4, and 2B15; aldoketoreductase (AKR) 1C1, 1B10, and 1C4; and cytochrome P450 (CYP450) 3A4, 2C8, and 1A2. When coadministered with itraconazole, a potent CYP450 3A4 inhibitor, lumateperone peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 3.5- and 4-fold, respectively. When coadministered with diltiazem, a moderate CYP450 3A4 inhibitor, lumateperone Cmax and AUC increased by approximately 2- and 2.5-fold, respectively. No data are available for other, less potent CYP450 3A4 inhibitors.

MANAGEMENT: Caution is advised when lumateperone is used with CYP450 3A4 inhibitors. Patients should be monitored for increased adverse effects such as extrapyramidal symptoms, tardive dyskinesia, hyperglycemia, dyslipidemia, hyperprolactinemia, neutropenia, leukopenia, orthostatic hypotension, syncope, seizures, cognitive and motor impairment, dysphagia, and heat-related illnesses due to disruption of body temperature regulation.

GENERALLY AVOID: Grapefruit and grapefruit juice may increase the plasma concentrations of lumateperone. 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 but has been reported for other CYP450 3A4 inhibitors. In a drug interaction study, the strong CYP450 3A4 inhibitor itraconazole increased lumateperone peak plasma concentration (Cmax) and systemic exposure (AUC) approximately 3.5- and 4-fold, respectively, while diltiazem (a moderate CYP450 3A4 inhibitor) increased lumateperone Cmax and AUC approximately 2- and 2.5-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.

When administered with a high-fat meal, lumateperone Cmax decreased by 33% while its AUC increased by 9% and its median time to peak plasma concentration (Tmax) was delayed by about 1 hour.

MANAGEMENT: Lumateperone should be administered with food. Coadministration of grapefruit or grapefruit juice with lumateperone should be avoided.