Lumateperone

Lumateperone
Names
Pronunciation/luːməˈtɛpərɑːn/
loo-mə-TE-pə-ron
Caplyta kəp-LY-tə
Trade namesCaplyta
Other namesLumateperone tosylate, 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
Clinical data
Drug classAtypical antipsychotic[1]
Main usesSchizophrenia[1]
Side effectsSleepiness, dry mouth[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Routes of
use		By mouth
Typical dose42 mg OD[1]
External links
AHFS/Drugs.comMonograph
MedlinePlusa620014
Legal
License data
Legal status
Pharmacokinetics
Bioavailability4.4%[2]
Protein binding97.4%[2]
MetabolismMultiple UGTs, CYP450s, and AKR enzymes[2]
Excretion<1% excreted unchanged in urine[2]
Chemical and physical data
FormulaC24H28FN3O
Molar mass393.506 g·mol−1
3D model (JSmol)
SMILES
  • [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 a medication used to treat schizophrenia.[1] It is taken by mouth.[2]

Common side effects include sleepiness and dry mouth.[1] Other side effects may include neuroleptic malignant syndrome, tardive dyskinesia, diabetes, weight gain, low white blood cells, seizures, and poor coordination.[2] It increases the risk of death in older people with dementia.[2] It is a atypical antipsychotic.[2]

was approved for medical use in the United States in 2019.[1] In the United States it costs about 1,400 USD per month as of 2021.[3]

Medical uses

Schizophrenia

Lumateperone is used to treat schizophrenia in adults.[4][5]

Dosage

Lumateperone is at a dose of 42 mg dose (60 mg lumateperone tosylate), despite being studied at lower doses (14 and 28 mg) and a higher dose (84 mg).[2]

Pharmacology

Receptor affinities[2]
ReceptorKi (nM)
5-HT2A0
 .54
Dopamine receptor D141
Serotonin transporter33
Dopamine receptor D232
Dopamine receptor D4<100
Alpha-1A adrenergic receptor<100
Alpha-1B adrenergic receptor<100

Mechanism of action

Lumateperone acts as an antagonist of 5-HT2A receptor and antagonizes several dopamine receptor subtypes (D1, D2, and D4). It has moderate serotonin transporter reuptake inhibition. It has additional off-target antagonism at alpha-1 receptors, without appreciable antimuscarinic or antihistaminergic properties.[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

Lumateperone was approved for medical use in the United States in December 2019,[4][5] and became available in February 2020.[2]

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]

Society and culture

Economics

The failure of Study 401 caused Intra-Cellular's stock price to fall.[6][7] Their stock fell again on July 23, when the US Food and Drug Administration (FDA) canceled a Psychopharmacologic Drugs Advisory Committee meeting.[8][9]

Research

Bipolar

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][7] the data pertaining this trial is due out in 2020.[12][7]

Study 401 was conducted solely in the United States while Study 404 was a global study and included patients from the US. 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.[13][14] 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.[15]

References

  1. 1 2 3 4 5 6 7 "Lumateperone Monograph for Professionals". Drugs.com. Archived from the original on 19 January 2021. Retrieved 24 November 2021.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 "Caplyta- lumateperone capsule". DailyMed. Intra-Cellular Therapies, Inc. 27 December 2019. Archived from the original on 4 July 2020. Retrieved 3 July 2020.
  3. ↑ "Lumateperone Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 24 November 2021.
  4. 1 2 3 4 5 6 7 8 9 10 11 "Drug Trials Snapshots: Caplyta". U.S. Food and Drug Administration. 20 December 2019. Archived from the original on 4 August 2020. Retrieved 2 July 2020. Public Domain 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. Archived from the original on 2 July 2020. Retrieved 1 July 2020.
  6. ↑ House DW, ed. (8 July 2019). "Intra-Cellular down 9% premarket on uneven results from lumateperone studies". Seeking Alpha. Retrieved 6 November 2019.
  7. 1 2 3 "Why Intra-Cellular Therapies Is Tanking Today". finance.yahoo.com. Archived from the original on 22 March 2021. Retrieved 6 November 2019.
  8. ↑ "Lumateperone schizophrenia drug seems to hit snag". www.mdedge.com. Archived from the original on 7 August 2020. Retrieved 6 November 2019.
  9. ↑ "Lumateperone for schizophrenia shows safety, tolerability in long-term study". www.mdedge.com. Archived from the original on 26 January 2020. Retrieved 6 November 2019.
  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. Archived from the original on 6 November 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. Archived from the original on 6 November 2019. Retrieved 6 November 2019 – via GlobeNewswire.
  12. ↑ "One out of two is not enough for Intra-Cellular". Evaluate.com. 8 July 2019. Archived from the original on 6 November 2019. Retrieved 6 November 2019.
  13. ↑ "One out of two is not enough for Intra-Cellular". Evaluate.com. 8 July 2019. Archived from the original on 6 November 2019. Retrieved 6 November 2019.
  14. ↑ DeArment A (8 July 2019). "Intra-Cellular Therapies hits one, misses another in Phase III bipolar disorder program". MedCity News. Archived from the original on 1 November 2021. Retrieved 6 November 2019.
  15. ↑ "Phase 3 data supports lumateperone for bipolar depression". www.healio.com. 8 July 2019. Archived from the original on 31 October 2021. Retrieved 6 November 2019.
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