lumateperone
{{Short description|Atypical antipsychotic}}
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{{Use dmy dates|date=January 2020}}
{{Infobox drug
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| image = ITI-007.svg
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| pronounce = {{IPAc-en|ˌ|l|uː|m|ə|ˈ|t|ɛ|p|ə|r|oʊ|n}}
{{respell|LOO|mə|TE|pər|ohn}}
| tradename = Caplyta
| Drugs.com = {{drugs.com|monograph|lumateperone-tosylate}}
| MedlinePlus = a620014
| DailyMedID = Lumateperone
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| routes_of_administration = By mouth
| class = Atypical antipsychotic
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| ATC_prefix = N05
| ATC_suffix = AD10
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| legal_US = Rx-only
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| metabolism = Multiple UGTs, CYP450s, and AKR enzymes
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| excretion = <1% excreted unchanged in urine
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 313368-91-1
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| PubChem = 9821941
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| DrugBank = DB06077
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| ChemSpiderID = 7997690
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| UNII = 70BSQ12069
| KEGG = D11169
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| synonyms = ITI-007; ITI-722
| IUPAC_name = 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
| C=24 | H=28 | F=1 | N=3 | O=1
| SMILES = [H] [C@]12CCN(CCCC(=O)C3=CC=C(F)C=C3)C[C@@]1([H])C1=CC=CC3=C1N2CCN3C
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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). It is developed by Intra-Cellular Therapies, licensed from Bristol-Myers Squibb.{{cite book| veditors = Celanire S, Poli S |title=Small Molecule Therapeutics for Schizophrenia|url=https://books.google.com/books?id=HEzPBAAAQBAJ&pg=PA31|date=13 October 2014|publisher=Springer|isbn=978-3-319-11502-3|pages=31–}} Lumateperone was approved for medical use in the United States in December 2019 with an initial indication for schizophrenia, and became available in February 2020. 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.
Medical uses
= Schizophrenia =
On December 20, 2019, the United States Food and Drug Administration (FDA) approved lumateperone for the treatment of schizophrenia in adults.{{cite web | title=Drug Trials Snapshots: Caplyta | website=U.S. Food and Drug Administration (FDA) | date=20 December 2019 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-caplyta | archive-url=https://web.archive.org/web/20200804152617/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-caplyta | url-status=dead | archive-date=4 August 2020 | access-date=2 July 2020}} {{PD-notice}}{{cite web | title=Drug Approval Package: Caplyta | website=U.S. Food and Drug Administration (FDA) | date=21 January 2020 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209500Orig1s000TOC.cfm | archive-url=https://web.archive.org/web/20200403061320/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209500Orig1s000TOC.cfm | url-status=dead | archive-date=3 April 2020 | access-date=1 July 2020}}{{cite press release | title=FDA Approves Intra-Cellular Therapies' Novel Antipsychotic, Caplyta (lumateperone) for the Treatment of Schizophrenia in Adults | publisher=Intra-Cellular Therapies Inc. | via=GlobeNewswire | date=23 December 2019 | url=http://www.globenewswire.com/news-release/2019/12/23/1963993/0/en/FDA-Approves-Intra-Cellular-Therapies-Novel-Antipsychotic-CAPLYTA-lumateperone-for-the-Treatment-of-Schizophrenia-in-Adults.html | access-date=1 July 2020}}
=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.{{Cite web|url=https://ir.intracellulartherapies.com/news-releases/news-release-details/intra-cellular-therapies-announces-us-fda-approval-caplytar|title=Intra-Cellular Therapies Announces U.S. FDA Approval of CAPLYTA® (Lumateperone) for the Treatment of Bipolar Depression in Adults | Intra-Cellular Therapies Inc}} 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.{{drugs.com|pro|Caplyta}}
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.{{cite book |title=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury |date=2012 |publisher=National Institute of Diabetes and Digestive and Kidney Diseases |url=https://www.ncbi.nlm.nih.gov/books/NBK574493/ |chapter=Lumateperone|pmid=34648250 }} {{PD-notice}}
Pharmacology
= Mechanism of action =
Lumateperone acts as an antagonist at 5-HT2A receptors and binds to several dopamine receptors (D1, D2, and D4) with moderate affinity. It has moderate serotonin transporter reuptake inhibition, which is partly responsible for its antidepressant effect in bipolar disorder and reduction of negative symptoms of schizophrenia.{{cite book | vauthors = Cooper D, Gupta V | chapter = Lumateperone |date=2025 | title = StatPearls | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK560844/ |access-date=2025-04-16 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32809679 }} It may also inhibit dopamine transporter reuptake, but more evidence is needed to confirm this.{{cite journal | vauthors = Tarzian M, Ndrio M, Chique B, Serai J, Thalackal B, Lau J, Fakoya AO | title = Illuminating Hope for Mental Health: A Drug Review on Lumateperone | journal = Cureus | volume = 15 | issue = 9 | pages = e46143 | date = September 2023 | pmid = 37900490 | pmc = 10612995 | doi = 10.7759/cureus.46143 | doi-access = free }} It has additional off-target antagonism at α1 receptors, without appreciable antimuscarinic or antihistaminergic properties, limiting side effects associated with other atypical antipsychotics, notably metabolic syndrome and hyperprolactinemia.{{cite web | title= Caplyta- lumateperone capsule | website=DailyMed.nlm.nih.gov| date=27 December 2019 | url= https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=db730b06-6351-47fd-8183-e61e61bbead5 | publisher= National Library of Medicine, National Institutes of Health | location = US| access-date=3 July 2020}}
Similar to aripiprazole, lumateperone acts as a partial agonist at inhibitory D2 autoreceptors and an antagonist at postsynaptic D2 receptors, thereby simultaneously reducing dopamine release and binding to postsynaptic receptors, respectively. However, lumateperone only occupies around 39% of D2 receptors—compared to at least 60-80% D2 occupancy for most antipsychotics to work for psychosis—and displays regioselectivity for the mesolimbic pathway, whose hyperactivity is responsible for the positive symptoms of schizophrenia. This reduces the risk of extrapyramidal symptoms (EPS) from reduced dopaminergic transmission in the nigrostriatal pathway.{{cite journal | vauthors = Syed AB, Brašić JR | title = The role of lumateperone in the treatment of schizophrenia | journal = Therapeutic Advances in Psychopharmacology | volume = 11 | pages = 20451253211034019 | date = 2021 | pmid = 34377435 | pmc = 8326816 | doi = 10.1177/20451253211034019 }}
A mechanism that is shared by all other atypical antipsychotics is antagonism of 5HT2A receptors, but, uniquely, lumateperone’s affinity for these receptors is 60x higher than its affinity for D2 receptors. This makes it a highly effective treatment for negative and cognitive symptoms of schizophrenia since 5HT2A antagonism increases dopamine release in the mesocortical pathway, which is hypoactive in those with schizophrenia.
Interestingly, lumateperone indirectly augments glutamatergic neurotransmission through its activity at D1 receptors, which causes phosphorylation of GluN2B subunits of NMDA receptors in the mesolimbic pathway. This is significant since NMDA receptor hypofunction, reduced D1 binding, and glutamatergic abnormalities have been implicated in contributing to the cognitive and negative symptoms of schizophrenia.{{cite journal | vauthors = Edinoff A, Wu N, deBoisblanc C, Feltner CO, Norder M, Tzoneva V, Kaye AM, Cornett EM, Kaye AD, Viswanath O, Urits I | title = Lumateperone for the Treatment of Schizophrenia | journal = Psychopharmacology Bulletin | volume = 50 | issue = 4 | pages = 32–59 | date = September 2020 | pmid = 33012872 | pmc = 7511146 }}
= 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. 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).
Lumateperone does not cause appreciable inhibition of any common CYP450 enzymes. It is not a substrate for p-glycoprotein.
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. The trials were conducted at 33 sites in the United States. Trials 1 and 2 provided data on the benefits and side effects of lumateperone, and Trial 3 provided data on side effects only.
Three trials provided data for the approval of lumateperone. 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). Neither the participants nor the health care providers knew which treatment was being given until after the trials were completed.
Trials 1 and 2 provided data for the assessment of benefits and side effects through four weeks of therapy. Benefit was assessed by measuring the overall improvement in the symptoms of schizophrenia. Trial 3 provided data for the assessment of side effects only during six weeks of therapy.
Two Phase III lumateperone monotherapy studies were conducted and completed for the treatment of bipolar depression, those being trial Study 401 and Study 404.{{Cite press release |url=http://www.globenewswire.com/news-release/2019/07/08/1879347/0/en/Intra-Cellular-Therapies-Announces-Positive-Top-line-Results-from-a-Phase-3-Trial-of-Lumateperone-in-Patients-with-Bipolar-Depression.html|title=Intra-Cellular Therapies Announces Positive Top-line Results from a Phase 3 Trial of Lumateperone in Patients with Bipolar Depression | publisher = Intra-Cellular Therapies Inc. |date=2019-07-08|via=GlobeNewswire |access-date=2019-11-06}} A third trial, Study 402, aims to test lumateperone in addition to lithium or valproate,{{Cite press release|url=http://www.globenewswire.com/news-release/2019/07/08/1879347/0/en/Intra-Cellular-Therapies-Announces-Positive-Top-line-Results-from-a-Phase-3-Trial-of-Lumateperone-in-Patients-with-Bipolar-Depression.html|title=Intra-Cellular Therapies Announces Positive Top-line Results from a Phase 3 Trial of Lumateperone in Patients with Bipolar Depression | publisher = Intra-Cellular Therapies Inc. |date=2019-07-08|via=GlobeNewswire |access-date=2019-11-06}}{{Cite web|url=https://finance.yahoo.com/news/why-intra-cellular-therapies-tanking-153400209.html|title=Why Intra-Cellular Therapies Is Tanking Today|website=Yahoo! Finance|date=8 July 2019 |access-date=2019-11-06}} the data pertaining this trial is due out in 2020.{{Cite web|url=https://www.evaluate.com/vantage/articles/news/trial-results/one-out-two-not-enough-intra-cellular|title=One out of two is not enough for Intra-Cellular|date=2019-07-08|website=Evaluate|access-date=2019-11-06}}
Study 401 was conducted solely in the United States while Study 404 was a global study and included patients from the US.{{Cite web|url=https://www.evaluate.com/vantage/articles/news/trial-results/one-out-two-not-enough-intra-cellular|title=One out of two is not enough for Intra-Cellular|date=2019-07-08|website=Evaluate|access-date=2019-11-06}}{{cite web |url= https://medcitynews.com/2019/07/intra-cellular-therapies-hits-one-misses-another-in-phase-iii-bipolar-disorder-program/|title=Intra-Cellular Therapies hits one, misses another in Phase III bipolar disorder program| vauthors = DeArment A | date=2019-07-08|website=MedCity News|access-date=2019-11-06}} 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.{{Cite web|url=https://www.evaluate.com/vantage/articles/news/trial-results/one-out-two-not-enough-intra-cellular|title=One out of two is not enough for Intra-Cellular|date=2019-07-08|website=Evaluate|access-date=2019-11-06}}{{cite web |url= https://medcitynews.com/2019/07/intra-cellular-therapies-hits-one-misses-another-in-phase-iii-bipolar-disorder-program/|title=Intra-Cellular Therapies hits one, misses another in Phase III bipolar disorder program| vauthors = DeArment A | date=2019-07-08|website=MedCity News|access-date=2019-11-06}} 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.{{Cite web |url= https://www.healio.com/psychiatry/bipolar-disorder/news/online/%7Be849adff-1dbf-4f3e-9642-71d78ad12195%7D/phase-3-data-supports-lumateperone-for-bipolar-depression |title=Phase 3 data supports lumateperone for bipolar depression|date = 8 July 2019 |website=Healio |access-date=2019-11-06}}
References
{{reflist}}
External links
- {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/lumateperone | publisher = U.S. National Library of Medicine| work = Drug Information Portal | title = Lumateperone }}
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Category:Atypical antipsychotics
Category:4-Fluorophenyl compounds