Lumateperone

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Lumateperone
ITI-007.svg
Clinical data
Pronunciation /ˌluːməˈtɛpəroʊn/
LOO-mə-TE-pər-ohn
Trade names Caplyta
Other namesITI-007; ITI-722
AHFS/Drugs.com Monograph
MedlinePlus a620014
License data
Routes of
administration 		By mouth
Drug class Atypical antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 4.4% [2]
Protein binding 97.4% [2]
Metabolism Multiple UGTs, CYP450s, and AKR enzymes [2]
Excretion <1% excreted unchanged in urine [2]
Identifiers
  • 1-(4-Fluorophenyl)-4-(3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-butanone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C24H28FN3O
Molar mass 393.506 g·mol−1
3D model (JSmol)
  • [H] [C@]12CCN(CCCC(=O)C3=CC=C(F)C=C3)C[C@@]1([H])C1=CC=CC3=C1N2CCN3C

Lumateperone, sold under the brand name Caplyta, is an atypical antipsychotic medication of the butyrophenone class. It is approved for the treatment of schizophrenia as well as bipolar depression, as either monotherapy or adjunctive therapy (with lithium or valproate). [2] It is developed by Intra-Cellular Therapies, licensed from Bristol-Myers Squibb. [3] Lumateperone was approved for medical use in the United States in December 2019 with an initial indication for schizophrenia, [4] [5] and became available in February 2020. [2] It has since demonstrated efficacy in bipolar depression and received FDA approval in December 2021 for depressive episodes associated with both bipolar I and II disorders. Part of the drug shows structural similarity to Pirlindole.

Contents

Medical uses

Schizophrenia

On December 20, 2019, the United States Food and Drug Administration (FDA) approved lumateperone for the treatment of schizophrenia in adults. [4] [5] [6]

Bipolar depression

In December 2021, the FDA approved lumateperone for the treatment of bipolar depression in adults as monotherapy and as adjunctive therapy with lithium or valproate. [2] [7] The number needed to treat (NNT) for bipolar depression at a dose of 42 mg daily is 7 patients.

Adverse effects

The most common adverse effects (≥5%) were somnolence and dry mouth. [8]

Lumateperone is associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent acute liver injury. [9]

Pharmacology

Receptor affinities [2]
SiteKi (nM)
SERT 33
5-HT2A 0.54
α1A <100
α1B <100
D1 41
D2 32
D4 <100

Mechanism of action

Lumateperone acts as a receptor antagonist of 5-HT2A receptor and antagonizes several dopamine receptors (D1, D2, and D4) with lower affinity. It has moderate serotonin transporter reuptake inhibition. It has additional off-target antagonism at α1 receptors, without appreciable antimuscarinic or antihistaminergic properties, limiting side effects associated with other atypical antipsychotics. [2]

Pharmacokinetics

After taking the medication by mouth, lumateperone reaches maximum plasma concentrations within 1–2 hours and has a terminal elimination half-life of 18 hours. [2] Lumateperone is a substrate for numerous metabolic enzymes, including various glucuronosyltransferase (UGT) isoforms (UGT1A1, 1A4, and 2B15), aldo-keto reductase (AKR) isoforms (AKR1C1, 1B10, and 1C4), and cytochrome P450 (CYP) enzymes (CYP3A4, 2C8, and 1A2). [2]

Lumateperone does not cause appreciable inhibition of any common CYP450 enzymes. It is not a substrate for p-glycoprotein. [2]

History

The FDA approved lumateperone based on evidence from three clinical trials (Trial 1/NCT01499563, Trial 2/NCT02282761 and Trial 3/NCT02469155) that enrolled 818 adult participants with schizophrenia. [4] The trials were conducted at 33 sites in the United States. [4] Trials 1 and 2 provided data on the benefits and side effects of lumateperone, and Trial 3 provided data on side effects only. [4]

Three trials provided data for the approval of lumateperone. [4] In each trial, hospitalized participants with schizophrenia were randomly assigned to receive either lumateperone or a comparison treatment (placebo or active comparator) once daily for four weeks (Trials 1 and 2) or six weeks (Trial 3). [4] Neither the participants nor the health care providers knew which treatment was being given until after the trials were completed. [4]

Trials 1 and 2 provided data for the assessment of benefits and side effects through four weeks of therapy. [4] Benefit was assessed by measuring the overall improvement in the symptoms of schizophrenia. [4] Trial 3 provided data for the assessment of side effects only during six weeks of therapy. [4]

Two Phase III lumateperone monotherapy studies were conducted and completed for the treatment of bipolar depression, those being trial Study 401 and Study 404. [10] A third trial, Study 402, aims to test lumateperone in addition to lithium or valproate, [11] [12] the data pertaining this trial is due out in 2020. [13] [12]

Study 401 was conducted solely in the United States while Study 404 was a global study and included patients from the US. [14] [15] Of the entire Study 404 population (381 patients), two-thirds were from Russia and Colombia. At the completion of the two monotherapy Phase III trials only Study 404 met its primary endpoint and one of its secondary endpoints. [16] [17] In Study 404, patients received 42 mg lumateperone once daily or placebo for six weeks. Study 404 patients saw an improvement of depressive symptoms compared to placebo as documented by a change in MADRS total score of 4.6. [18]

Related Research Articles

<span class="mw-page-title-main">Antipsychotic</span> Class of medications

Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of psychotropic medication primarily used to manage psychosis, principally in schizophrenia but also in a range of other psychotic disorders. They are also the mainstay, together with mood stabilizers, in the treatment of bipolar disorder. Moreover, they are also used as adjuncts in the treatment of treatment-resistant major depressive disorder.

<span class="mw-page-title-main">Mood stabilizer</span> Psychiatric medication used to treat mood disorders

A mood stabilizer is a psychiatric medication used to treat mood disorders characterized by intense and sustained mood shifts, such as bipolar disorder and the bipolar type of schizoaffective disorder.

<span class="mw-page-title-main">Haloperidol</span> Typical antipsychotic medication

Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosis, and hallucinations from alcohol withdrawal. It may be used by mouth or injection into a muscle or a vein. Haloperidol typically works within 30 to 60 minutes. A long-acting formulation may be used as an injection every four weeks for people with schizophrenia or related illnesses, who either forget or refuse to take the medication by mouth.

<span class="mw-page-title-main">Atypical antipsychotic</span> Class of pharmaceutical drugs

The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs largely introduced after the 1970s and used to treat psychiatric conditions. Some atypical antipsychotics have received regulatory approval for schizophrenia, bipolar disorder, irritability in autism, and as an adjunct in major depressive disorder.

<span class="mw-page-title-main">Risperidone</span> Antipsychotic medication

Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder, as well as irritability associated with autism. It is taken either by mouth or by injection. The injectable versions are long-acting and last for 2–4 weeks.

<span class="mw-page-title-main">Quetiapine</span> Atypical antipsychotic medication

Quetiapine, sold under the brand name Seroquel among others, is an atypical antipsychotic medication used for the treatment of schizophrenia, bipolar disorder, and major depressive disorder. Despite being widely used as a sleep aid, the benefits of such use may not outweigh the risk of undesirable side effects. It is taken orally.

<span class="mw-page-title-main">Olanzapine</span> Atypical antipsychotic medication

Olanzapine, sold under the brand name Zyprexa among others, is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. It is also sometimes used off-label for treatment of chemotherapy-induced nausea and vomiting and as an appetite stimulant. For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is taken by mouth or by injection into a muscle.

<span class="mw-page-title-main">Aripiprazole</span> Atypical antipsychotic

Aripiprazole, sold under the brand names Abilify and Aristada, among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder; other uses include as an add-on treatment in major depressive disorder and obsessive–compulsive disorder (OCD), tic disorders, and irritability associated with autism. Aripiprazole is taken by mouth or via injection into a muscle. A Cochrane review found low-quality evidence of effectiveness in treating schizophrenia.

<span class="mw-page-title-main">Lamotrigine</span> Medication used for bipolar disorder, epilepsy, & many seizure disorders

Lamotrigine, sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut syndrome. In bipolar disorder, lamotrigine has not been shown to reliably treat acute depression in any groups except for the severely depressed; but for patients with bipolar disorder who are not currently symptomatic, it appears to reduce the risk of future episodes of depression.

The emphasis of the treatment of bipolar disorder is on effective management of the long-term course of the illness, which can involve treatment of emergent symptoms. Treatment methods include pharmacological and psychological techniques.

<span class="mw-page-title-main">Asenapine</span> Medication to treat schizophrenia

Asenapine, sold under the brand name Saphris among others, is an atypical antipsychotic medication used to treat schizophrenia and acute mania associated with bipolar disorder as well as the medium to long-term management of bipolar disorder.

<span class="mw-page-title-main">Iloperidone</span> Atypical antipsychotic medication

Iloperidone, commonly known as Fanapt and previously known as Zomaril, is an atypical antipsychotic for the treatment of schizophrenia and bipolar I disorder.

<span class="mw-page-title-main">Lurasidone</span> Atypical antipsychotic medication

Lurasidone, sold under the brand name Latuda among others, is an antipsychotic medication used to treat schizophrenia and bipolar depression. It is taken by mouth.

<span class="mw-page-title-main">Pimavanserin</span> Atypical antipsychotic medication

Pimavanserin, sold under the brand name Nuplazid, is an atypical antipsychotic which is approved for the treatment of Parkinson's disease psychosis. Unlike other antipsychotics, pimavanserin is not a dopamine receptor antagonist, but rather is a selective inverse agonist of the serotonin 5-HT2A receptor.

<span class="mw-page-title-main">Ecopipam</span> Investigational dopamine antagonist

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<span class="mw-page-title-main">Cariprazine</span> Atypical antipsychotic medicine

Cariprazine, sold under the brand name Vraylar among others, is an atypical antipsychotic developed by Gedeon Richter, which is used in the treatment of schizophrenia, bipolar mania, bipolar depression, and major depressive disorder. It acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors, with high selectivity for the D3 receptor. It is taken by mouth. The most prevalent side effects include nausea, mild sedation, fatigue, and dizziness. At higher dosages, there is an increased risk for restlessness, insomnia, and tremors.

<span class="mw-page-title-main">Brexpiprazole</span> Atypical antipsychotic

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<span class="mw-page-title-main">Samidorphan</span> Opioid antagonist

Samidorphan is an opioid antagonist that in the form of olanzapine/samidorphan is used in the treatment of schizophrenia and bipolar disorder. Samidorphan reduces the weight gain associated with olanzapine. Samidorphan is taken by mouth.

<span class="mw-page-title-main">Ulotaront</span> Investigational antipsychotic drug

Ulotaront is an investigational antipsychotic that is undergoing clinical trials for the treatment of schizophrenia and Parkinson's disease psychosis. The medication was discovered in collaboration between PsychoGenics Inc. and Sunovion Pharmaceuticals using PsychoGenics' behavior and AI-based phenotypic drug discovery platform, SmartCube. Ulotaront is in Phase III of clinical development.

References

  1. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Caplyta- lumateperone capsule". DailyMed.nlm.nih.gov. US: National Library of Medicine, National Institutes of Health. 27 December 2019. Retrieved 3 July 2020.
  3. ↑ Celanire S, Poli S, eds. (13 October 2014). Small Molecule Therapeutics for Schizophrenia. Springer. pp. 31–. ISBN   978-3-319-11502-3.
  4. 1 2 3 4 5 6 7 8 9 10 11 "Drug Trials Snapshots: Caplyta". U.S. Food and Drug Administration (FDA). 20 December 2019. Retrieved 2 July 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  5. 1 2 "Drug Approval Package: Caplyta". U.S. Food and Drug Administration (FDA). 21 January 2020. Retrieved 1 July 2020.
  6. ↑ "FDA Approves Intra-Cellular Therapies' Novel Antipsychotic, Caplyta (lumateperone) for the Treatment of Schizophrenia in Adults" (Press release). Intra-Cellular Therapies Inc. 23 December 2019. Retrieved 1 July 2020– via GlobeNewswire.
  7. ↑ "Intra-Cellular Therapies Announces U.S. FDA Approval of CAPLYTA® (Lumateperone) for the Treatment of Bipolar Depression in Adults | Intra-Cellular Therapies Inc".
  8. ↑ FDA Professional Drug Information
  9. ↑ "Lumateperone". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012. PMID   34648250.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  10. ↑ "Intra-Cellular Therapies Announces Positive Top-line Results from a Phase 3 Trial of Lumateperone in Patients with Bipolar Depression" (Press release). Intra-Cellular Therapies Inc. 8 July 2019. Retrieved 6 November 2019– via GlobeNewswire.
  11. ↑ "Intra-Cellular Therapies Announces Positive Top-line Results from a Phase 3 Trial of Lumateperone in Patients with Bipolar Depression" (Press release). Intra-Cellular Therapies Inc. 8 July 2019. Retrieved 6 November 2019– via GlobeNewswire.
  12. 1 2 "Why Intra-Cellular Therapies Is Tanking Today". Yahoo! Finance. 8 July 2019. Retrieved 6 November 2019.
  13. ↑ "One out of two is not enough for Intra-Cellular". Evaluate. 8 July 2019. Retrieved 6 November 2019.
  14. ↑ "One out of two is not enough for Intra-Cellular". Evaluate. 8 July 2019. Retrieved 6 November 2019.
  15. ↑ DeArment A (8 July 2019). "Intra-Cellular Therapies hits one, misses another in Phase III bipolar disorder program". MedCity News. Retrieved 6 November 2019.
  16. ↑ "One out of two is not enough for Intra-Cellular". Evaluate. 8 July 2019. Retrieved 6 November 2019.
  17. ↑ DeArment A (8 July 2019). "Intra-Cellular Therapies hits one, misses another in Phase III bipolar disorder program". MedCity News. Retrieved 6 November 2019.
  18. ↑ "Phase 3 data supports lumateperone for bipolar depression". Healio. 8 July 2019. Retrieved 6 November 2019.
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