Asenapine

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Asenapine
Skeletal formula of asenapine
Ball-and-stick model of the asenapine molecule
Systematic (IUPAC) name
(3aRS,12bRS)-rel-5-Chloro-2,3,3a,12b-tetrahydro-
2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
Clinical data
Trade names Saphris, Sycrest
AHFS/Drugs.com monograph
MedlinePlus a610015
Licence data EMA:Link, US FDA:link
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Routes of
administration		 sublingual
Pharmacokinetic data
Bioavailability 35% (sublingual), <2% (Oral)[1][2][3][4]
Protein binding 95%[1][2][3][4]
Metabolism hepatic (glucurinodation by UGT1A4 and oxidative metabolism by CYP1A2)[1][2][3][4]
Biological half-life 24 hours[1][2][3][4]
Excretion Renal (50%), Faecal (40%; ~5-16% as unchanged drug in faeces)[1][2][3][4]
Identifiers
CAS Number 65576-45-6 N
ATC code N05AH05 (WHO)
PubChem CID: 163091
IUPHAR/BPS 22
ChemSpider 2300725 YesY
UNII JKZ19V908O YesY
ChEBI CHEBI:71253 N
ChEMBL CHEMBL1201756 N
Chemical data
Formula C17H16ClNO
Molecular mass 285.77 g/mol
  • Clc4cc2c(Oc1c(cccc1)[C@@H]3CN(C[C@@H]23)C)cc4
  • InChI=1S/C17H16ClNO/c1-19-9-14-12-4-2-3-5-16(12)20-17-7-6-11(18)8-13(17)15(14)10-19/h2-8,14-15H,9-10H2,1H3/t14-,15-/m0/s1 YesY
  • Key:VSWBSWWIRNCQIJ-GJZGRUSLSA-N YesY
 NYesY (what is this?)  (verify)

Asenapine (USAN, rINNM and BANM;[5] trade names Saphris (AU, US, RU), Sycrest (EU, UK)) is an atypical antipsychotic developed for the treatment of schizophrenia and acute mania associated with bipolar disorder by Schering-Plough after its November 19, 2007 merger with Organon International. Development of the drug, through Phase III trials, began while Organon was still a part of Akzo Nobel.[6] Preliminary data indicate that it has minimal anticholinergic and cardiovascular side effects, as well as minimal weight gain. Over 3000 patients have participated in clinical trials of asenapine, and the FDA approved the manufacturer's NDA in August 2009.[7]

It was chemically derived via altering the chemical structure of the tetracyclic (atypical) antidepressant, mianserin.[8]

Medical uses

Asenapine has been approved by the FDA for the acute treatment of adults with schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults.[9] In Australia asenapine's approved (and also listed on the PBS) indications include the following:[10]

  • Schizophrenia
  • Treatment, for up to 6 months, of an episode of acute mania or mixed episodes associated with bipolar I disorder
  • Maintenance treatment, as monotherapy, of bipolar I disorder

In the European Union and the UK asenapine is only licensed for use as a treatment for acute mania in bipolar I disorder.[3][4]

Absorbed readily if administered sublingually, asenapine is poorly absorbed when swallowed.[11] It appears to be less efficacious than other antipsychotics in the treatment of schizophrenia,[12] although its all-cause discontinuation rate is moderate.[12] As for its efficacy in the treatment of acute mania, a recent meta-analysis showed that it produces comparatively small improvements in manic symptoms in patients with acute mania and mixed episodes than most other antipsychotic drugs (with the exception of ziprasidone) such as risperidone and olanzapine. Drop-out rates (in clinical trials) were also unusually high with asenapine.[13] According to a post-hoc analysis of two 3-week clinical trials it may possess some antidepressant effects in patients with acute mania or mixed episodes.[14]

Adverse effects

Adverse effect incidence[1][2][3][4]
Note: The discussion below these lists provides some more context into the frequency and severity of these adverse effects.

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

Common (1-10% incidence) adverse effects include:

Uncommon (0.1-1% incidence) adverse effects include:

Rare (0.01-0.1% incidence) adverse effects include:

Unknown incidence adverse effects

  • Allergic reaction
  • Restless legs syndrome
  • Nausea
  • Oral mucosal lesions (ulcerations, blistering and inflammation)
  • Salivary hypersecretion
  • Hyperprolactinaemia


Asenapine seems to have a relatively low weight gain liability for an atypical antipsychotic (which are notorious for their metabolic side effects) and according to a recent meta-analysis it produces significantly less weight gain (SMD [standard mean difference in weight gained in those on placebo vs. active drug]: 0.23; 95% CI: 0.07-0.39) than, paliperidone (SMD: 0.38; 95% CI: 0.27-0.48), risperidone (SMD: 0.42; 95% CI: 0.33-0.50), quetiapine (SMD: 0.43; 95% CI: 0.34-0.53), sertindole (SMD: 0.53; 95% CI: 0.38-0.68), chlorpromazine (SMD: 0.55; 95% CI: 0.34-0.76), iloperidone (SMD: 0.62; 95% CI: 0.49-0.74), clozapine (SMD: 0.65; 95% CI: 0.31-0.99), zotepine (SMD: 0.71; 95% CI: 0.47-0.96) and olanzapine (SMD: 0.74; 95% CI: 0.67-0.81) and approximately (that is, no statistically significant difference at the p=0.05 level) as much as weight gain as aripiprazole (SMD: 0.17; 95% CI: 0.05-0.28), lurasidone (SMD: 0.10; 95% CI: –0.02-0.21), amisulpride (SMD: 0.20; 95% CI: 0.05-0.35), haloperidol (SMD: 0.09; 95% CI: 0.00-0.17) and ziprasidone (SMD: 0.10; 95% CI: –0.02-0.22).[12] Its potential for elevating plasma prolactin levels seems relatively limited too according to this meta-analysis.[12] This meta-analysis also found that asenapine has approximately the same odds ratio (3.28; 95% CI: 1.37-6.69) for causing sedation [compared to placebo-treated patients] as olanzapine (3.34; 95% CI: 2.46-4.50]) and haloperidol (2.76; 95% CI: 2.04-3.66) and a higher odds ratio (although not significantly) for sedation than aripiprazole (1.84; 95% CI: 1.05-3.05), paliperidone (1.40; 95% CI: 0.85-2.19) and amisulpride (1.42; 95% CI: 0.72 to 2.51) to name a few and is hence a mild-moderately sedating antipsychotic.[12] Being a second-generation (atypical) antipsychotic its liability for causing extrapyramidal side effect is comparatively low compared to first-generation antipsychotics such as haloperidol as is supported by the aforementioned meta-analysis (although this meta-analysis did reveal it had a relatively high EPS liability for an atypical antipsychotic drug).[12]

Pharmacology

Asenapine shows high affinity (pKi) for numerous receptors, including the serotonin 5-HT1A (8.6), 5-HT1B (8.4), 5-HT2A (10.2), 5-HT2B (9.8), 5-HT2C (10.5), 5-HT5A (8.8), 5-HT6 (9.5), and 5-HT7 (9.9) receptors, the adrenergic α1 (8.9), α2A (8.9), α2B (9.5), and α2C (8.9) receptors, the dopamine D1 (8.9), D2 (8.9), D3 (9.4), and D4 (9.0) receptors, and the histamine H1 (9.0) and H2 (8.2) receptors. It has much lower affinity (pKi < 5) for the muscarinic acetylcholine receptors. Asenapine behaves as a partial agonist at the 5-HT1A receptors.[16] At all other targets Asenapine is an antagonist.[17] As of November 2010 Asenapine is also in clinical trials at UC Irvine to treat stuttering.

Receptor Affinity (pKi)[17] Affinity (Ki (nM))[9]
5-HT1A 8.6 (agonist) 2.5 (agonist)
5-HT1B 8.4 4.0
5-HT2A 10.2 0.06
5-HT2B 9.8 0.16
5-HT2C 10.5 0.03
5-HT5A 8.8 1.6
5-HT6 9.5 0.25
5-HT7 9.9 0.13
α1-Adrenergic 8.9 1.2
α2A-Adrenergic 8.9 1.2
α2B-Adrenergic 9.5 0.32
α2C-Adrenergic 8.9 1.2
D1 8.9 1.4
D2 8.9 1.3
D3 9.4 0.42
D4 9.0 1.1
H1 9.0 1.0
H2 8.2 6.2
mACh < 5 8,128

Synthesis

Asenapine scheme.png

J. van der Burg, U.S. Patent 4,145,434.

Reduction step is sodium in liquid ammonia.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Truven Health Analytics, Inc. MARTINDALE - The Complete Drug Reference (Internet) [cited 2013 Sep 30]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ 9.0 9.1 Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ http://cat.inist.fr/?aModele=afficheN&cpsidt=21237275
  17. ↑ 17.0 17.1 Lua error in package.lua at line 80: module 'strict' not found.

External links

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