Lumateperone

Uses

Lumateperone is a novel 2nd generation antipsychotic used to manage both positive and negative symptoms in patients with schizophrenia.

Lumateperone is approved for the treatment of schizophrenia in adults.

Lumateperone is also used to associated treatment for these conditions: Schizophrenia

How Lumateperone works

There is much to learn about the pathophysiology of schizophrenia; however, dopamine abnormalities, specifically in the prefrontal and mesolimbic brain regions, are consistent in people with schizophrenia. In addition to dopamine, other neurotransmitters such as serotonin, glutamate, GABA and acetylcholine are thought to play a role.

Lumateperone is unique among second generation antipsychotics based on its target profile and dopamine D2 receptor occupancy. Unlike other antipsychotics, lumateperone has partial agonist activity at presynaptic dopamine (D2) receptors, resulting in reduced presynaptic release of dopamine, and antagonistic activity at postsynaptic dopamine (D2) receptors. These characteristics allow lumateperone to efficiently reduce dopamine signaling.

Lumateperone also targets dopamine (D1) receptors, and a useful secondary result of D1 activation is increased glutamatergic N-methyl-D-aspartate (NMDA) GluN2B receptor phosphorylation. This is significant since NMDA mediated glutamate signaling appears to be impaired in patients who have schizophrenia.

Finally, lumateperone is capable of modulating serotonin by inhibiting serotonin transporters (SERT), and by behaving as a 5-HT2A receptor antagonist.

Toxicity

Since lumateperone is a newly approved medication, there is no post-marketing data available at this time. It is likely that symptoms of toxicity will include more intense lumateperone adverse effects such as excessive sedation.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of lumateperone, which may increase its serum concentration.
• Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of lumateperone, causing a reduction in its serum concentration.
• Take with food. Administration with food reduces the Cmax by 33% and prolongs the Tmax by one hour.

[Moderate] 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.

Lumateperone Alcohol interaction

[Moderate] GENERALLY AVOID:

Alcohol may potentiate some of the pharmacologic effects of central nervous system (CNS)-active agents.

Use in combination may result in additive CNS depression and/or impairment of judgment, thinking, and psychomotor skills.

Patients receiving CNS-active agents should be advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled against driving, operating machinery, or engaging in potentially hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Lumateperone Cholesterol interaction

[Moderate] Atypical antipsychotic drugs have been associated with undesirable alterations in lipid levels.

While all agents in the class have been shown to produce some changes, each drug has its own specific risk profile.

Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment.

Lumateperone Drug Interaction

Major: carbamazepineModerate: aripiprazole, benztropine, duloxetine, venlafaxine, lurasidone, fluphenazine, risperidone, quetiapineUnknown: docusate, pentosan polysulfate sodium, multivitamin with iron, psyllium, polyethylene glycol 3350, omega-3 polyunsaturated fatty acids, famotidine, clopidogrel, dabigatran, multivitamin, prenatal, pantoprazole

Lumateperone Disease Interaction

Major: dementia, hepatic impairment, tardive dyskinesiaModerate: aspiration, seizure, hematologic abnormalities, hyperglycemia/diabetes, hypotension, lipid alterations

Volume of Distribution

The volume of distribution of lumateperone is approximately 4.1 L/Kg after intravenous administration.

Elimination Route

Lumateperone is able to permeate multidrug resistance protein 1 (MDR1) and is very lipophilic at a pH of 7.4, which are characteristics that allow the antipsychotic to be absorbed in the small intestine and the blood brain barrier. Tmax occurs 3-4 hours after oral administration.

Half Life

Lumateperone's half life is reported to be between 13 to 18 hours. The reported half lives of the metabolites ICI200161 and ICI200131, are 20 and 21 hours respectively.

Clearance

Lumateperone's clearance is estimated to be 27.9 L/hour.

Elimination Route

Due to it's molecular weight, virtually all unchanged lumateperone is excreted in the feces. Lumateperone's metabolites are very water soluble which is a property that allows for complete elimination. Approximately 58% of a lumateperone dose can be recovered in the urine, while 29% can be recovered in the feces.

Innovators Monograph

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