Sertindole

Last updated

Sertindole
Sertindole.svg
Sertindole ball-and-stick model.png
Clinical data
Trade names Serdolect, Serlect
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • AU:C
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 75% [1]
Protein binding 99.5% [1]
Metabolism Liver (mostly via CYP2D6 and CYP3A4) [2] [3]
Elimination half-life 3 days [2]
Excretion Faecal (the majority), Kidney (4% metabolites; 1% unchanged) [2]
Identifiers
  • 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-indol-3-yl]-1-piperidyl]ethyl]imidazolidin-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.162.562 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H26ClFN4O
Molar mass 440.95 g·mol−1
3D model (JSmol)
  • Fc1ccc(cc1)n3c2ccc(Cl)cc2c(c3)C5CCN(CCN4C(=O)NCC4)CC5
  • InChI=1S/C24H26ClFN4O/c25-18-1-6-23-21(15-18)22(16-30(23)20-4-2-19(26)3-5-20)17-7-10-28(11-8-17)13-14-29-12-9-27-24(29)31/h1-6,15-17H,7-14H2,(H,27,31) Yes check.svgY
  • Key:GZKLJWGUPQBVJQ-UHFFFAOYSA-N Yes check.svgY
   (verify)

Sertindole, sold under the brand name Serdolect among others, is an antipsychotic medication. Sertindole was developed by the Danish pharmaceutical company Lundbeck and marketed under license by Abbott Labs. Like other atypical antipsychotics, it has activity at dopamine and serotonin receptors in the brain. It is used in the treatment of schizophrenia. It is classified chemically as a phenylindole derivative.

Contents

Sertindole is not approved for use in the United States and was discontinued in Australia in January 2014.[ citation needed ]

Medical Uses

Sertindole appears effective as an antipsychotic in schizophrenia. [4] In a 2013 study in a comparison of 15 antipsychotic drugs in effectivity in treating schizophrenic symptoms, sertindole was found to be slightly less effective than haloperidol, quetiapine, and aripiprazole, as effective as ziprasidone, approximately as effective as chlorpromazine and asenapine, and slightly more effective than lurasidone and iloperidone. [5]

Adverse effects

Very common (>10% incidence) adverse effects include: [2]

Common (1–10% incidence) adverse effects include: [2]

Uncommon (0.1–1% incidence) adverse effects include: [2]

Rare (<0.1% incidence) adverse effects include: [2]

Unknown frequency adverse events include: [2]

Pharmacology

Biologic proteinBinding affinity (Ki[nM]) [7] Notes
5-HT1A 280
5-HT1B 60
5-HT1D 96
5-HT1E 430
5-HT1F 360
5-HT2A 0.39The receptor believed to mediate the atypicality of atypical antipsychotics. [8]
5-HT2C 0.9Likely responsible for its propensity for causing weight gain. [8]
5-HT6 5.4
5-HT7 28
α1A 1.8Likely responsible for the orthostatic hypotension seen in patients on sertindole. [8]
α2A 640
α2B 450
α2C 450
β1 5000
β2 5000
M1 >10000 [8]
M3 2692
D2 2.35Believed to be responsible for the drug's efficacy against positive symptoms. [8]
D3 2.30
D4 4.92
hERG 3Responsible for the QT interval prolongation and torsade de pointes
H1 130
NK1 1000

Sertindole is metabolized in the body to dehydrosertindole. [9]

Safety and status

United States

Abbott Labs first applied for U.S. Food and Drug Administration (FDA) approval for sertindole in 1996, [10] but withdrew this application in 1998 following concerns over the increased risk of sudden death from QTc prolongation. [11] In a trial of 2000 patients on taking sertindole, 27 patients died unexpectedly, including 13 sudden deaths. [12] Lundbeck cites the results of the Sertindole Cohort Prospective (SCoP) study of 10,000 patients to support its claim that although sertindole does increase the QTc interval, this is not associated with increased rates of cardiac arrhythmias, and that patients on sertindole had the same overall mortality rate as those on risperidone. [13] Nevertheless, in April 2009 an FDA advisory panel voted 13-0 that sertindole was effective in the treatment of schizophrenia but 12-1 that it had not been shown to be acceptably safe. [14] As of October 2010, the drug has not been approved by the FDA for use in the USA. [15] [ failed verification ]

European Union

In the European Union, sertindole was approved and marketed in 19 countries from 1996, [12] but its marketing authorization was suspended by the European Medicines Agency in 1998 [16] and the drug was withdrawn from the market. In 2002, based on new data, the EMA's CHMP suggested that Sertindole could be reintroduced for restricted use in clinical trials, with strong safeguards including extensive contraindications and warnings for patients at risk of cardiac dysrhythmias, a recommended reduction in maximum dose from 24 mg to 20 mg in all but exceptional cases, and extensive ECG monitoring requirement before and during treatment. [17] [18] As of September 2020, sertindole is authorized in several countries of the European Union. [19]

References

  1. 1 2 Karamatskos E, Lambert M, Mulert C, Naber D (November 2012). "Drug safety and efficacy evaluation of sertindole for schizophrenia". Expert Opinion on Drug Safety. 11 (6): 1047–62. doi:10.1517/14740338.2012.726984. PMID   22992213. S2CID   11339387.
  2. 1 2 3 4 5 6 7 8 "PRODUCT INFORMATION SERDOLECT TABLETS" (PDF). TGA eBusiness Services. Lundbeck Australia Pty Ltd. 16 January 2013. Retrieved 27 October 2013.
  3. ↑ Juruena MF, de Sena EP, de Oliveira IR (May 2011). "Sertindole in the management of schizophrenia". Journal of Central Nervous System Disease. 3: 75–85. doi:10.4137/JCNSD.S5729. PMC   3663609 . PMID   23861640.
  4. ↑ Lewis R, Bagnall AM, Leitner M (July 2005). "Sertindole for schizophrenia". The Cochrane Database of Systematic Reviews. 2005 (3): CD001715. doi:10.1002/14651858.CD001715.pub2. PMC   7025766 . PMID   16034864.
  5. 1 2 3 4 5 6 Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet. 382 (9896): 951–62. doi:10.1016/S0140-6736(13)60733-3. PMID   23810019. S2CID   32085212.
  6. 1 2 Taylor D, Paton C, Shitij K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN   978-0-470-97948-8.
  7. ↑ Roth BL, Driscol J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from the original on 8 November 2013. Retrieved 27 October 2013.
  8. 1 2 3 4 5 Brunton L, Chabner B, Knollman B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN   978-0-07-162442-8.
  9. ↑ "TRC | Details of CAS = 173294-84-3, ChemicalName = Dehydrosertindole, synonym = 1-[2-[4-[5-Chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-1,3-dihydro-2H-Imidazol-2-one; Lu 28-092, MolFormula = C24H24ClFn4O". Archived from the original on 27 April 2015. Retrieved 20 April 2015.
  10. ↑ Zeneca's Seroquel Nears Market Approval - The Pharma Letter, 16 July 1997
  11. ↑ Abbott Labs Withdraws Sertindole NDA Sertindole - The Pharma Letter, 12 January 1998
  12. 1 2 "WHO Pharmaceuticals Newsletter 1998, No. 03&04: Regulatory actions: Sertindole - approval application withdrawn". Archived from the original on 22 June 2011.
  13. ↑ FDA Advisory Committee provides opinion on Serdolect for the treatment of schizophrenia Archived 14 July 2011 at the Wayback Machine - Lundbeck press release, 8 April 2009
  14. ↑ Food and Drug Administration; Minutes of the Psychphamacological Drugs Advisory Committee, 7 Apr 2009
  15. ↑ "Welcome to Lundbeck's global site".
  16. ↑ EU CHMP recommends lifting ban on atypical antipsychotic Serdolect (sertindole) Archived 2 October 2011 at the Wayback Machine - National electronic Library for Medicines, NHS
  17. ↑ COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS OPINION FOLLOWING AN ARTICLE 36 REFERRAL: SERTINDOLE Archived 4 March 2016 at the Wayback Machine - European Medicines Agency, 13 September 2002
  18. ↑ Restricted re-introduction of the atypical antipsychotic sertindole (Serdolect) Archived 17 November 2010 at the Wayback Machine - MHRA, 2002
  19. ↑ Sertindole: List of nationally authorised medicinal products - PSUSA/00002695/202001 (PDF) (Report). European Medicines Agency (EMA). 3 September 2020. EMA/270645/2015.
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