Central 5-HT 2A and D 2 dopamine receptor occupancy after sublingual administration of ORG 5222 in healthy men

Andrée, Bengt; Halldin, Christer; Vries, Maria Vrijmoed-de; Farde, Lars

doi:10.1007/s002130050301

Cited by 24 publications

(11 citation statements)

References 33 publications

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“…Additional studies have been undertaken that directly compare asenapine with olanzapine in patients with schizophrenia, but the principal results of these studies have not yet been published. However, discontinuation rates for one 52-week trial (study 25517) are available in the FDA briefing document (5), and on the measure of allcause discontinuation, olanzapine had an advantage over asenapine with a NNT of 6 (95% CI [4][5][6][7][8][9]. This is consistent with the observation that in one of the short-term schizophrenia trials (041021), olanzapine demonstrated efficacy vs. placebo but asenapine did not.…”

Section: -8mentioning

confidence: 53%

“…Of these, only one was a clinical trial report (6), the remainder included a post hoc evaluation of dropouts in six placebo-controlled short-term trials (7), a paper describing clinical trial design and rationale for the treatment of negative symptoms (8), a positron emission tomography (PET) study in healthy subjects (9), 31 papers describing preclinical laboratory and animal experiments and 12 reviews of which only one focused exclusively on asenapine (10). Query of http://www.fda.gov resulted in the acquisition of two principal documents, a briefing book for the FDA Psychopharmacologic Drugs Advisory Committee prepared by FDA staff (5) and a briefing document prepared by Schering-Plough Corporation (11).…”

Section: Study Selectionmentioning

confidence: 99%

“…Although the uniqueness of asenapine's receptor signature can be quantified using cloned human receptors (17), actual correlations with observed clinical effects needs to be assessed in people, and one direct method is with PET. Several PET studies have been performed (5), of which one has been published (9). Asenapine demonstrates dose-dependent dopamine D2 receptor occupancy (dose range 0.1-4.8 mg) with a significant correlation between D2 occupancy and plasma concentration (5).…”

Section: Data Synthesismentioning

confidence: 99%

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Asenapine for schizophrenia and bipolar disorder: a review of the efficacy and safety profile for this newly approved sublingually absorbed second-generation antipsychotic

Citrome

2009

International Journal of Clinical Practice

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Objective: To describe the efficacy and safety of asenapine for the treatment of schizophrenia and bipolar disorder. Data sources: The pivotal registration trials were accessed by querying http://www.pubmed.gov, http://www.fda.gov and http:// www.clinicaltrials.gov for the search terms 'asenapine' or 'ORG 5222'. Study selection: All available clinical reports of studies were identified, as well as preclinical animal and receptor affinity studies that describe potential mechanisms of action. Extensive documents available from the US Food and Drug Administration and Schering-Plough Corporation as posted on http://www.fda.gov provided much of this data. Product labelling also provided additional information. Data extraction: Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the study reports and synopses. Additional safety outcomes subject to NNH analysis were obtained from product labelling. Data synthesis: A sublingual formulation of asenapine has received regulatory approval for the acute treatment of schizophrenia and manic ⁄ mixed episodes of bipolar I disorder. Bioavailability is 35% when taken sublingually, but < 2% if ingested. Similar to other second-generation antipsychotics, asenapine's binding profile includes 5-HT2A and D2 antagonism. Binding at the alpha-1 adrenergic and histamine H1 receptors predicts asenapine's propensity to cause orthostasis and sedation in some patients. Efficacy in the treatment of acute schizophrenia is supported by 2 of 4 completed phase II ⁄ III randomised, placebo and active-controlled 6-week trials, principally at a dose of 5 mg bid. Responder analysis for one of the studies reveals a NNT of asenapine vs. placebo of six for response as defined by a minimum of a 20% decrease in the Positive and Negative Syndrome Scale total score from baseline, and a NNT of 8 for the threshold of a 30% decrease. Efficacy in the treatment of manic or mixed episodes of bipolar I disorder is supported by 2 of 2 completed phase III randomised, placebo and active-controlled 3-week trials and by a 9-week extension trial. The dose tested in the bipolar trials was 10 mg bid. Longer-term studies have been completed in patients with schizophrenia or bipolar disorder, but complete results have not yet been published. Asenapine has a relatively favourable tolerability profile. For the patients with schizophrenia, the NNH values for asenapine vs. placebo for commonly observed adverse reactions were 13 (95% CI 8-30) for akathisia (10 mg bid), 20 (95% CI 13-50) for oral hypoesthesia (5 mg bid) and 13 (95% CI 8-32) for somnolence (5 mg bid). For patients with bipolar disorder, the NNH values for asenapine 5-10 mg bid vs. placebo were 6 (95% CI 5-9) for somnolence, 13 (95% CI 9-25) for dizziness, 20 (95% CI 13-56) for extra-pyramidal symptoms (EPS) other than akathisia and 25 (95% CI 16-71) for increased weight. Asenapine is associated with a lower frequency for EPS than haloperidol. Asen...

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Section: -8mentioning

confidence: 53%

Section: Study Selectionmentioning

confidence: 99%

Section: Data Synthesismentioning

confidence: 99%

See 1 more Smart Citation

Asenapine for schizophrenia and bipolar disorder: a review of the efficacy and safety profile for this newly approved sublingually absorbed second-generation antipsychotic

Citrome

2009

International Journal of Clinical Practice

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“…Although data from both PET and single-photon emission computed tomography (SPECT) studies could be used to ascertain receptor occupancy levels, in the present models, only PET data were used because there were only limited SPECT data that included plasma concentration observations. All of the PET studies used 11 C-raclopride as the radioligand, except for one in-house PET study with asenapine that used NCQ-115 (12).…”

Section: Dopamine D 2 Receptor Occupancymentioning

confidence: 99%

“…In an unpublished phase II study, sublingual asenapine doses up to 0.8 mg twice daily (BID) did not reduce symptoms of schizophrenia compared with placebo. In PET studies of healthy subjects, low D 2 occupancy was observed after the administration of sublingual asenapine doses of up to 0.3 mg BID (11,12), but D 2 receptor occupancy achieved more appropriate levels of 68-93% in patients with schizophrenia after administration of asenapine Electronic supplementary material The online version of this article (doi:10.1208/s12248-010-9247-4) contains supplementary material, which is available to authorized users.…”

Section: Introductionmentioning

confidence: 99%

Dopamine D2 Occupancy as a Biomarker for Antipsychotics: Quantifying the Relationship with Efficacy and Extrapyramidal Symptoms

Greef

Maloney

Gisleskog

et al. 2010

AAPS J

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Abstract. For currently available antipsychotic drugs, blockade of dopamine D 2 receptors is a critical component for achieving antipsychotic efficacy, but it is also a driving factor in the development of extrapyramidal symptoms (EPS). To inform the clinical development of asenapine, generic mathematical models have been developed for predicting antipsychotic efficacy and EPS tolerability based on D 2 receptor occupancy. Clinical data on pharmacokinetics, D 2 receptor occupancy, efficacy, and EPS for several antipsychotics were collected from the public domain. Asenapine data were obtained from inhouse trials. D 2 receptor occupancy data were restricted to published positron emission tomography studies that included blood sampling for pharmacokinetics. Clinical efficacy data were restricted to group mean endpoint data from short-term placebo-controlled trials, whereas EPS evaluation also included some non-placebo-controlled trials. A generally applicable model connecting antipsychotic dose, pharmacokinetics, D 2 receptor occupancy, Positive and Negative Syndrome Scale (PANSS) response, and effect on Simpson-Angus Scale (SAS) was then developed. The empirical models describing the D 2 -PANSS and D 2 -SAS relationships were used successfully to aid dose selection for asenapine phase II and III trials. A broader use can be envisaged as a dose selection tool for new antipsychotics with D 2 antagonist properties in the treatment of schizophrenia.

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Pharmacology and Neuroscience of Antipsychotic Drugs

2010

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Central 5-HT 2A and D 2 dopamine receptor occupancy after sublingual administration of ORG 5222 in healthy men

Cited by 24 publications

References 33 publications

Asenapine for schizophrenia and bipolar disorder: a review of the efficacy and safety profile for this newly approved sublingually absorbed second-generation antipsychotic

Asenapine for schizophrenia and bipolar disorder: a review of the efficacy and safety profile for this newly approved sublingually absorbed second-generation antipsychotic

Dopamine D2 Occupancy as a Biomarker for Antipsychotics: Quantifying the Relationship with Efficacy and Extrapyramidal Symptoms

Pharmacology and Neuroscience of Antipsychotic Drugs

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