Out Of The Pipeline

Asenapine for schizophrenia and bipolar I disorder

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Receptor binding profile and sublingual delivery distinguish asenapine from other atypical antipsychotics


 

References

In August 2009, the FDA approved asenapine for treating acute exacerbation of schizophrenia and acute manic or mixed episodes of bipolar disorder with or without psychosis in adults (Table 1). Asenapine is the first psychotropic to obtain simultaneous FDA approval for schizophrenia and bipolar disorder. The drug’s unique receptor binding profile shows promise in treatment of positive and negative symptoms of schizophrenia with a low risk of extrapyramidal and anticholinergic side effects.

Table 1

Asenapine: Fast facts

Brand name: Saphris
Indications: Acute schizophrenia in adults; acute mixed or manic episodes with or without psychosis associated with bipolar I disorder in adults
Approval date: August 2009
Availability date: Late 2009
Manufacturer: Schering-Plough
Dosing forms: 5-mg and 10-mg sublingual dissolvable tablets
Recommended dose: Schizophrenia: 5 mg twice daily; bipolar disorder: 10 mg twice daily

How it works

Asenapine is an atypical antipsychotic. Although the exact mechanism of these medications’ efficacy is unknown, their antipsychotic and antimanic activity is thought to be the result of antagonism of central dopamine receptors. According to dopamine theory proposed in the 1960s:

  • dopaminergic hyperactivity in mesolimbic dopaminergic pathways contributes to positive symptoms of schizophrenia—hallucinations, delusions, disorganized thoughts and behaviors, and catatonia
  • dopaminergic hypoactivity in mesocortical dopaminergic pathways (prefrontal cortex) contributes to negative symptoms of schizophrenia—alogia, avolition, anhedonia, autism, social withdrawal, attention problems, blunted affect, and abstract thinking difficulty.

Asenapine has high affinity for multiple dopamine, serotonin, noradrenergic α1 and α2, and histamine H1 receptors, where it works as an antagonist. Asenapine’s affinity for several serotonin, noradrenergic, and dopaminergic D3 and D4 receptors is higher than its affinity for D2 receptors (Table 2),1 which distinguishes asenapine from other atypical antipsychotics except clozapine.

Blockade of 5-HT2A and 5-HT2C receptors in prefrontal cortex increases dopamine release in this area; theoretically, this effect should improve negative symptoms. Another mechanism that possibly improves cognition and negative symptoms is asenapine’s antagonism at central α2 noradrenergic receptors. Central α1 noradrenergic receptor antagonism also might be helpful in improving positive symptoms of schizophrenia.1

Asenapine’s affinity for the muscarinic-1 cholinergic receptors is quite low, and adverse effects associated with antagonism at these receptors—dry mouth, blurred vision, constipation, and urinary retention—are minimal.2

Table 2

Asenapine’s binding affinity for receptor subtypes*

Receptor substypeAffinity [Ki (nM)]
5-HT2A0.06
5-HT2C0.03
D11.4
D21.3
D30.42
D41.1
α11.2
α21.2
H11.0
M18128
*Lower numbers indicate higher affinity
5-HT: serotonin receptors; D1-4: dopamine receptors; α1, α2: noradrenergic receptors; H1: histamine receptor; M1: muscarinic (cholinergic) receptor
Source: Reference 1

Pharmacokinetics

Absorption of asenapine after oral (swallowed) administration is 2%. To increase total bioavailability to 35%, the drug is manufactured as sublingual dissolvable tablets. After sublingual administration, asenapine is readily absorbed and achieves peak plasma concentration in approximately 1 hour. After absorption, 95% of asenapine binds to transport proteins albumin and α1 acid glycoprotein. The half-life of the medication is approximately 24 hours, and steady state usually is achieved in 3 days.

Metabolism creates about 40 metabolites via multiple metabolic pathways; the main ones are glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 (CYP)1A2. Asenapine is a weak inhibitor of CYP2D6, so coadministration of asenapine with other drugs that are substrates or inhibitors of CYP1A2 (eg, fluvoxamine) or CYP2D6 (eg, paroxetine, fluoxetine) should be done cautiously. Because asenapine elimination is biphasic, twice-daily dosing is recommended.3

Efficacy in clinical trials

Schizophrenia. Asenapine’s efficacy for treating schizophrenia was evaluated in 3 fixed-dose, 6-week, randomized, double-blind, placebo- and active- (haloperidol, olanzapine, and risperidone) controlled clinical trials in adults.3-5 Subjects in these studies met DSM-IV criteria for schizophrenia and had acute exacerbation of their illness, with Positive and Negative Syndrome Scale (PANSS) total scores ≥60. Symptom improvement was measured after 6 weeks by PANSS total score, PANSS positive subscale, and Clinical Global Impression scale (CGI).

The first trial (n=174) compared asenapine, 5 mg twice daily, to placebo and risperidone, 3 mg twice daily.3-5 Asenapine was superior to placebo as demonstrated by symptom improvement on all 3 scales. Risperidone showed statistically significant symptom improvement on PANSS positive subscale and CGI but not on PANSS total score.

In the second trial (n=448), 2 fixed doses of asenapine (5 mg twice daily and 10 mg twice daily) and olanzapine, 15 mg/d, were compared with placebo.3,5 The only statistically significant symptom improvement in the asenapine group compared with placebo was on the PANSS positive subscale among subjects receiving 5 mg twice daily. Improvements measured by CGI and PANSS total score were not statistically significant.

Olanzapine showed statistically significant symptom improvement on all 3 scales compared with placebo. This study is a negative trial for asenapine; asenapine failed to separate from placebo, whereas olanzapine—the active comparator—did.

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