Lurasidone

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Lurasidone
Lurasidone.svg
Ball-and-stick model of the lurasidone molecule
Clinical data
Trade names Latuda
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a611016
License data
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Routes of
administration
Oral
ATC code N05AE05 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 9–19% (oral)[1]
Metabolism Hepatic (CYP3A4-mediated)[1]
Biological half-life 18 hours[1]
Excretion Faecal (~80%), renal (~9%)[1]
Identifiers
Synonyms SM-13,496
CAS Number 367514-87-2
PubChem (CID) 213046
IUPHAR/BPS 7461
ChemSpider 184739
UNII 22IC88528T YesY
ChEBI CHEBI:70735 YesY
ChEMBL CHEMBL1237021
ECHA InfoCard 100.225.187
Chemical and physical data
Formula C28H36N4O2S
Molar mass 492.68 g/mol
3D model (Jmol) Interactive image
Specific rotation [α]20D −59°
Melting point 176 to 178 °C (349 to 352 °F)
Solubility in water 45 mg/mL (20 °C)

Lurasidone /lɜːr.ˈræ.sɪ.dn/ (trade name Latuda) is an atypical antipsychotic developed by Dainippon Sumitomo Pharma[2] and marketed by Sunovion in the USA. It has been approved for treatment of schizophrenia by the FDA since 2010. In the USA since 2013, it is also approved for the treatment of depressive episodes associated with bipolar I disorder as well as bipolar II disorder in adults when used alone or in combination with lithium, valproate, or lamotrigine.

Medical uses[edit]

Lurasidone is FDA approved for the treatment of schizophrenia since 2010[3] and depressive episodes associated with bipolar I disorder since 2013.[4] It received regulatory approval in the UK in September 2014. In October 2014, NHS Scotland advised use of lurasidone for schizophrenic adults who have not seen improvements with previous antipsychotics due to problems that arise from weight gain or changes in metabolic pathways when taking other medications.[5] It received EMA approval on January 24, 2014. It was launched in Canada for the treatment of schizophrenia in September 2012, Health Canada giving their Summary Basis of Decision (SBD) as favourable on October 15, 2012.[6] European Commission has granted a marketing authorization for once-daily oral lurasidone for the treatment of schizophrenia in adults.[7] It is approved for use in the EU.[8]

In July 2013 lurasidone received approval for bipolar I depression.[4] Few available atypical antipsychotics are known to possess antidepressant efficacy in bipolar disorder (with the notable exceptions being quetiapine,[9][10][11][12] olanzapine[13][14][15] and possibly asenapine[16]) as a monotherapy, even though the majority of atypical antipsychotics are known to possess significant antimanic activity,[17] which is yet to be clearly demonstrated for lurasidone.

Lurasidone may be useful for treating the cognitive and memory deficits seen in schizophrenia. In animal studies, it reversed dizocilpine-induced learning and memory impairment and was found to be superior in doing this to all of the other antipsychotics examined, including risperidone, olanzapine, quetiapine, clozapine, aripiprazole, and haloperidol.[18][19] Lurasidone has activity at several serotonin receptors that are involved in learning and memory, and unlike most other antipsychotics, lacks any anticholinergic effects (which are known to impair cognitive processes and memory).[18] These properties may underlie its improved effectiveness in treating these symptoms relative to older agents.[18]

Lurasidone is not approved by the Food and Drug Administration (FDA) for the treatment of behavior disorders in older adults with dementia.[citation needed]

Contraindications[edit]

Lurasidone is contraindicated in individuals who are taking strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir, levodropropizine, etc.) or inducers (carbamazepine, St. John's wort, phenytoin, rifampicin etc.).[20] The use of lurasidone in pregnant women has not been studied and is not recommended, although it should be noted that it is a category B drug.[21] Excretion in breast milk is also unknown; lurasidone is not recommended for breastfeeding women.[22] In the United States it is not indicated for use in children.[23]

Adverse effects[edit]

Side effects are generally similar to other antipsychotics. The drug has a relatively well-tolerated side effect profile, with low propensity for QTc interval changes, weight gain and lipid-related adverse effects.[24] In a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs it was found to produce the second least (after haloperidol) weight gain, the least QT interval prolongation, the fourth most extrapyramidal side effects (after haloperidol, zotepine and chlorpromazine) and the sixth least sedation (after paliperidone, sertindole, amisulpride, iloperidone and aripiprazole).[25]

As with other atypical neuroleptics, lurasidone should be used with caution in the elderly because it puts them at an increased risk for a stroke or transient ischemic attack;[26][27] however, these risks are not likely to be greater than those associated with antipsychotics of other classes.[28] Similarly, lurasidone should not be used to treat dementia-related psychosis, as evidence has shown increased mortality with antipsychotic use.[29]

Weight gain is reported in up to 15 and 16 percent of users.[30][31]

Pharmacology[edit]

Latuda is mainly blocking the D2 receptor (high affinity for D2 receptors). Also the dopamine D3 and D4-receptors have some importance.[32] Blocks of 5HT2A and 5HT7 receptor. High affinity for 5HT2A receptor and 5HT7, for those two. Partial agonism for the 5HT1A receptor. Low affinity for the 5HT2C receptor, 5HT3 and 5HT4-receptor. No affinity to H1-receptors.[33]

Latuda has high affinity for D2 receptors, 5HT2A and 5HT7 receptor. No affinity for the H1 receptor[33] and low affinity for 5HT2C explains the low weight gain, with latuda. However, there is an affinity for the 5HT3 receptor (but low affinity).[32][34][33][35][36]

Mechanism of action[edit]

Lurasidone acts as an antagonist of the following sites[18][34] with the exception of 5-HT1A, where it acts as a partial agonist.[18]

Receptor Affinity (Ki (nM))
α1-adrenergic receptor 48
α2A-adrenergic receptor 1.6
α2C-adrenergic receptor 10.8
D1 receptor 262
D2 receptor 0.9
D3 receptor 15.7
D4.4 receptor 30
5-HT2A receptor 2.0
5-HT2C receptor 415
5-HT3 receptor >1000
5-HT4 receptor >1000
5-HT7 receptor 0.5
5-HT1A receptor 6.8

Lurasidone has negligible actions at the H1 and mACh receptors.[18][37]

Pharmacokinetics[edit]

Studies have shown that when lurasidone is taken with food, absorption increases.[38]

Lurasidone is metabolized in the liver via the enzyme CYP3A4.[26] This means that its plasma concentrations may be increased when combined with CYP3A4 inhibitors like ketoconazole or grapefruit juice, possibly leading to more side effects. Co-administration of CYP3A4 inducers like rifampicin or St. John's wort can reduce plasma levels and consequently decrease the effects of the drug.

History[edit]

The FDA approved the drug in 2010.[32]

References[edit]

  1. ^ a b c d "PRODUCT INFORMATION LATUDA (lurasidone hydrochloride)" (PDF). TGA eBusiness Services. Therapeutic Goods Administration. 16 April 2014. Retrieved 1 May 2014. 
  2. ^ Meyer, Jonathan M; Loebel, Antony D; Schweizer, Edward (2009). "Lurasidone: A new drug in development for schizophrenia". Expert Opinion on Investigational Drugs. 18 (11): 1715–26. doi:10.1517/13543780903286388. PMID 19780705. 
  3. ^ "FDA approves Latuda to treat schizophrenia in adults" (Press release). USFDA. 2010-10-28. Retrieved October 29, 2010. 
  4. ^ a b Lowes R. Lurasidone Approved for Bipolar Depression [Internet]. Medscape. 2013 [cited 2013 Oct 2]. Available from: http://www.medscape.com/viewarticle/807204
  5. ^ "Lurasidone, 18.5mg, 37mg, 74mg film-coated tablets (Latuda) SMC No. (994/14)" (PDF). Scottish Medicines Consortium. 2014. 
  6. ^ "Summary Basis of Decision (SBD) for Latuda". Health Canada. 2012. 
  7. ^ "European Marketing Authorization for Latuda". takeda.com. Retrieved 25 November 2015. 
  8. ^ "European Medicines Agency - Find medicine - Latuda". europa.eu. Retrieved 25 November 2015. 
  9. ^ Young, Allan H.; McElroy, Susan L.; Bauer, Michael; Philips, Nabil; Chang, William; Olausson, Bengt; Paulsson, Björn; Brecher, Martin; EMBOLDEN I (Trial 001) Investigators (2010). "A Double-Blind, Placebo-Controlled Study of Quetiapine and Lithium Monotherapy in Adults in the Acute Phase of Bipolar Depression (EMBOLDEN I)". The Journal of Clinical Psychiatry. 71 (2): 150–62. doi:10.4088/JCP.08m04995gre. PMID 20122369. 
  10. ^ Suppes, Trisha; Datto, Catherine; Minkwitz, Margaret; Nordenhem, Arvid; Walker, Chris; Darko, Denis (2010). "Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression". Journal of Affective Disorders. 121 (1–2): 106–15. doi:10.1016/j.jad.2009.10.007. PMID 19903574. 
  11. ^ "Corrigendum". Bipolar Disorders. 10 (3): 451. 2008. doi:10.1111/j.1399-5618.2008.00585.x. 
  12. ^ Thase, ME (2008). "Quetiapine monotherapy for bipolar depression". Neuropsychiatric disease and treatment. 4 (1): 11–21. doi:10.2147/ndt.s1162. PMC 2515925Freely accessible. PMID 18728771. 
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  15. ^ Corya, Sara A.; Perlis, Roy H.; Keck Jr, Paul E.; Lin, Daniel Y.; Case, Michael G.; Williamson, Doug J.; Tohen, Mauricio F. (2006). "A 24-Week Open-Label Extension Study of Olanzapine-Fluoxetine Combination and Olanzapine Monotherapy in the Treatment of Bipolar Depression". The Journal of Clinical Psychiatry. 67 (5): 798–806. doi:10.4088/JCP.v67n0514. PMID 16841630. 
  16. ^ Azorin, J.M.; Sapin, C.; Weiller, E. (2013). "Effect of asenapine on manic and depressive symptoms in bipolar I patients with mixed episodes: Results from post hoc analyses". Journal of Affective Disorders. 145 (1): 62–9. doi:10.1016/j.jad.2012.07.013. PMID 22868059. 
  17. ^ Cipriani, Andrea; Barbui, Corrado; Salanti, Georgia; Rendell, Jennifer; Brown, Rachel; Stockton, Sarah; Purgato, Marianna; Spineli, Loukia M; Goodwin, Guy M; Geddes, John R (2011). "Comparative efficacy and acceptability of antimanic drugs in acute mania: A multiple-treatments meta-analysis". The Lancet. 378 (9799): 1306–15. doi:10.1016/S0140-6736(11)60873-8. PMID 21851976. 
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  19. ^ Enomoto, T; Ishibashi, T; Tokuda, K; Ishiyama, T; Toma, S; Ito, A (2008). "Lurasidone reverses MK-801-induced impairment of learning and memory in the Morris water maze and radial-arm maze tests in rats". Behavioural Brain Research. 186 (2): 197–207. doi:10.1016/j.bbr.2007.08.012. PMID 17881065. 
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  21. ^ Pregnancy category
  22. ^ "ACOG Practice Bulletin No. 92: Use of Psychiatric Medications During Pregnancy and Lactation". Obstetrics & Gynecology. 111 (4): 1001–20. 2008. doi:10.1097/AOG.0b013e31816fd910. PMID 18378767. 
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  25. ^ Leucht, Stefan; Cipriani, Andrea; Spineli, Loukia; Mavridis, Dimitris; Örey, Deniz; Richter, Franziska; Samara, Myrto; Barbui, Corrado; Engel, Rolf R; Geddes, John R; Kissling, Werner; Stapf, Marko Paul; Lässig, Bettina; Salanti, Georgia; Davis, John M (2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". The Lancet. 382 (9896): 951–62. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. 
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  27. ^ "Latuda". Drugs.com. Retrieved 2010-12-17. 
  28. ^ Herrmann, Nathan; Mamdani, Muhammad; Lanctôt, Krista L. (2004). "Atypical Antipsychotics and Risk of Cerebrovascular Accidents". American Journal of Psychiatry. 161 (6): 1113–5. doi:10.1176/appi.ajp.161.6.1113. PMID 15169702. 
  29. ^ Sunovion Pharmaceuticals. "Latuda Prescribing Information" (PDF). Latuda.com. Retrieved 25 March 2014. 
  30. ^ Meyer, Jonathan M.; Mao, Yongcai; Pikalov, Andrei; Cucchiaro, Josephine; Loebel, Antony (2015). "Weight change during long-term treatment with lurasidone". International Clinical Psychopharmacology. 30 (6): 342–50. doi:10.1097/YIC.0000000000000091. PMC 4593468Freely accessible. PMID 26196189. 
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  32. ^ a b c http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/200603Orig1s000PharmR.pdf
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  34. ^ a b Ishibashi, T.; Horisawa, T.; Tokuda, K.; Ishiyama, T.; Ogasa, M.; Tagashira, R.; Matsumoto, K.; Nishikawa, H.; Ueda, Y.; Toma, S.; Oki, H.; Tanno, N.; Saji, I.; Ito, A.; Ohno, Y.; Nakamura, M. (2010). "Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT7) and 5-HT1A Receptor Activity". Journal of Pharmacology and Experimental Therapeutics. 334 (1): 171–81. doi:10.1124/jpet.110.167346. PMID 20404009. 
  35. ^ Lincoln, Jana; Tripathi, Aveekshit (2011). "Lurasidone for Schizophrenia". Current Psychiatry. 10 (1): 67–70. 
  36. ^ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/200603Orig1s000PharmR.pdf[full citation needed]
  37. ^ Cite error: The named reference pmid27722855 was invoked but never defined (see the help page).
  38. ^ Latuda (lurasidone) [prescribing information]. Marlborough, MA: Sunovion Pharmaceuticals Inc.; July 2013.