Analyte Names and Structures:
Asenapine
asenapine.jpg
Relevant Physicochemical Data:
Asenapine is a dibenzo-oxepino pyrrole agent. The chemical designation is (3aRS,12bRS)—chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole(2Z)-2-butenediate (1:1). It is an off-white powder. The molecular formula for asenapine maleate is C17H16ClNO·C4H4O4 with a molecular weight of 401.84 (285.8 as the free base). [2]

Racemic mixture. Melting point 141-145
°C. UV max (ethanol 270 nm (e 1900). Soluble at 21°C (g/L) – water 3, ethanol 30, methanol 250, acetone 125, ethyl acetate 10, dichloromethane 250, hexamine <1. pH at 20°C (0.1% solution in water) is 4.56 and at 23°C (saturated solution 5.8 g/L) is 4.43. pK1 <3, pK2 7.52 and pK3 8.51. [12]

General Relevancy:
The FDA approved Asenapine (Saphrisâ) in August 2009 for the acute treatment of schizophrenia in adults, and for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Schizophrenia is a severe brain disorder affecting about 1.1% of the U.S. population age 18 and older in a given year.[3,4] The onset of symptoms in men usually develop in their late teens or early twenties, while in women they appear in their twenties and thirties. Only in rare cases do these symptoms appear in childhood. The symptoms typically include hallucinations, delusions, disorders in thinking and movement, flat affect, social withdrawal and cognitive deficits. Bipolar disorder causes unusual shifts in mood, energy, activity levels and the ability to perform daily tasks.[4,5] Symptoms are severe and are different from the normal ups and downs of everyday life. Bipolar I disorder (bipolar disorder with psychotic symptoms) affects about 1 % of adults and about 10 million Americans.[6]

Pharmacological treatment of schizophrenia and bipolar disorder I usually involve drugs that target dopamine D2 receptors. First generation conventional antipsychotic drugs (APD) introduced in the 1950’s are usually referred to as “typical”, because they typically produce extrapyramidal side-effects. They included such substances as chlorpromazine and haloperidol. These drugs have been effective in treating some of the symptoms of schizophrenia but have had limited efficacy on other aspects of the disorder and are associated with a high rate of extrapyramidal symptoms including parkinsonism, acute dystonia, akathisia and tardive dyskinesia. Clozapine was the first “atypical” APD introduced in the 1960s, but it was withdrawn in 1975 because of its association with agranulocytosis; however it was re-introduced in 1989 after its effectiveness was demonstrated in patients who failed to respond to typical APDs. Other atypical APDs include risperidone, olanzapine, quetiapine and ziprasidone. These drugs are not more effective than the “typical” APDs, but are better tolerated because of their lower tendency to cause extrapyramidal effects. However, atypical APDs are associated with weight gain, alterations in glucose and lipid metabolism, prolactin and QT interval prolongation. The majority (64-82%) of the patients stop using their medications because of inefficacy or adverse effects of these drugs. [4,7]


Asenapine is a psychotropic drug that displays a unique receptor binding profile. It has high affinity binding and antagonistic activity at a wide range of dopamine (D2 and D3), serotonin 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, 5-HT1A and 5-HT1B), norepinephrine (
a2-adrenergic) and histamine receptors (H1 and H2). [4,8,9] The efficacy of asenapine is thought to be mediated through a combination of potent antagonist activity at D2 and 5-HT2A receptors with the affinity to 5-HT2A receptors 19-times higher than that for D2 receptors.[4,8] Pre-clinical tests have shown a low tendency for the extrapyramidal effects.[7]


Asenapine is available in 5 and 10 mg dosage forms for sublingual administration twice daily. Significant fist-pass metabolism in the liver and probably the gut causing a bioavailability of less than 2% resulted in a change in the formulation from oral to sublingual administration.[8] [Note: Small differences in the kinetics of the tablet following administration at different sites of the oral cavity (sublingual, buccal and supralingual) were noted]. [8] Absorption of asenapine following sublingual administration is rapid with peak plasma concentrations occurring within 0.5 to 1.5 hours.[8] Mean peak plasma concentrations following a single sublingual dose of 5 mg have ranged from 3.0 to 5.2 ng/mL. [4,8,10] Doubling the dose from 5 mg to 10 mg twice-daily results in a less than a linear increase (1.7 times) in both the extent of exposure and maximum concentration. This deviation from dose-proportionality is more pronounced at supra-therapeutic doses (> 10 mg twice a day). Therapeutic and supra-therapeutic concentrations are highly bound to plasma proteins (95-97%) and the bioavailability with the sublingual dose is approximately 35%. Asenapine has a large volume of distribution (~ 20-25 L/kg) and has a high clearance of 52 L/hr following intravenous administration. [2,8] The terminal half-life of asenapine is approximately 24 hours and follows an initially more rapid distribution phase.[8] Steady state asenapine kinetics are similar those of the single dose and concentrations are reached within 3 days with two daily doses. [8]

Following the administration of a single dose of isotope-labeled asenapine, about 90% of the dose was recovered with approximately 50% in urine and 40% in feces. [8] Asenapine is extensively metabolized, mostly by uridine diphosphate-glucuronyl-transferase (UGT1A4) and cytochrome P450 isoenzymes (CYP1A2 and to a lesser extent CYP3A4 and CYP2D6).[4,8] About half of the plasma circulating species have been identified. The predominant species is asenapine N+-glucuronide; others include N-desmethylasenapine, N-desmethyl N-carbamoyl glucuronide and smaller amounts of unchanged asenapine. [8] Following a single 5 mg sublingual dose of asenapine, the Cmax values for asenapine N-glucuronide and N-desmethylasenapine were 5.34 and 0.39 ng/mL, respectively. [4,10] Since the metabolites do not penetrate the brain and/or have less affinity to receptors, the activity of the asenapine is primarily due to the parent drug. [4,8]

The most common adverse effects observed during treatment with asenapine include insomnia, somnolence, nausea, anxiety, agitation, headache, vomiting, constipation and psychosis.[4]


Proper Specimen Types:
Serum, plasma, whole blood, urine, tissues, fluids

Recommended Collection Tubes:
Nothing in the literature mentions a preferred sample container or preservative. Suitable container types are red top, grey top or lavender top tubes.

Analyte(s) to be Determined:

Since the parent drug asenapine is the active species, this should be the targeted analyte. (The inactive metabolites asenapine N-glucuronide and N-desmethylasenapine also have been measured in drug-interaction pharmacokinetic studies, but are mostly of academic interest [10,11] ).

Methods of Analysis:
LC/MS for asenapine and desmethylasenapine and LC-MS/MS for asenapine-N-glucuronide; [11] and LC-MS/MS for asenapine, desmethylasenapine and asenapine-N-glucuronide. [10]

Critical Concentrations:
The appropriate analytical range for this drug is 0.1 ng/mL to 25ng/mL. Mean peak plasma concentrations following a single sublingual dose of 5 mg have ranged from 3.0 to 5.2 ng/mL. [4,8,10] In a graph depicting a pharmacokinetic study following a 5-mg sublingual dose, the first plasma measurement appears to start at ~ 0.7 ng/mL, then peaks at ~ 3.2 ng/mL and declines to ~ 0.25 ng/mL at 24 hours post-dose.[8] Doubling the dose from 5 mg to 10 mg twice-daily results in a less than a linear increase (1.7 times) in maximum concentration. [8]

Stability Information:

No stability studies for asenapine in biological matrices were found in the literature reviewed.

Interpretative Comment(s):
Clinical:

Plasma/Serum: Mean peak plasma concentrations following a single sublingual dose of 5 mg asenapine have ranged from 3.0 to 5.2 ng/mL.

Blood: Mean peak plasma concentrations following a single sublingual dose of 5 mg asenapine have ranged from 3.0 to 5.2 ng/mL. The whole blood to plasma ratio for this drug has not been determined.

Urine: No urinary reference data for asenapine has been identified.

Forensic:

Serum/Plasma: Asenapine (Saphris
) is approved for the acute treatment of schizophrenia in adults and for the acute treatment of manic or mixed episodes associated with bipolar I disorder. It is available in 5 or 10 mg tablets for sublingual administration. The recommended frequency of dose is twice daily. Asenapine is metabolized to two inactive metabolites, asenapine N-glucuronide and N-desmethylasenapine

Mean peak plasma concentrations of asenapine following a single sublingual dose of 5 mg asenapine have ranged from 3.0 to 5.2 ng/mL

The most common adverse effects observed during treatment with asenapine include insomnia, somnolence, nausea, anxiety, agitation, headache, vomiting, constipation and psychosis.

Blood: Asenapine (Saphris
) is approved for the acute treatment of schizophrenia in adults and for the acute treatment of manic or mixed episodes associated with bipolar I disorder. It is available in 5 or 10 mg tablets for sublingual administration. The recommended frequency of dose is twice daily. Asenapine is metabolized to two inactive metabolites, asenapine N-glucuronide and N-desmethylasenapine

Mean peak plasma concentrations of asenapine following a single sublingual dose of 5 mg asenapine have ranged from 3.0 to 5.2 ng/mL. The whole blood to plasma ratio for this drug has not been determined.

The most common adverse effects observed during treatment with asenapine include insomnia, somnolence, nausea, anxiety, agitation, headache, vomiting, constipation and psychosis. The whole blood to plasma ratio for this drug has not been determined.

Urine: No urinary reference data for asenapine has been identified.

Tissue: Asenapine (Saphris
) is approved for the acute treatment of schizophrenia in adults and for the acute treatment of manic or mixed episodes associated with bipolar I disorder. It is available in 5 or 10 mg tablets for sublingual administration. The recommended frequency of dose is twice daily. Asenapine is metabolized to two inactive metabolites, asenapine N-glucuronide and N-desmethylasenapine. No reference concentrations are available for tissues.

Fluids: Asenapine (Saphris
) is approved for the acute treatment of schizophrenia in adults and for the acute treatment of manic or mixed episodes associated with bipolar I disorder. It is available in 5 or 10 mg tablets for sublingual administration. The recommended frequency of dose is twice daily. Asenapine is metabolized to two inactive metabolites, asenapine N-glucuronide and N-desmethylasenapine.

Citations for Reference Comments:
J Weber and PL McCormack. Asenapine. CNS Drugs. 2009;23(9):781-792.

FDA Psychopharmacologic Drugs Advisory Committee Meeting Saphris
â (asenapine) Sublingual Tablets (NDA 22-117). July 30, 2009. Advisory Committee Briefing Materials: Available for Public Release. Schering-Plough Research Institute, A Division of Schering Corporation. Kenilworth, NJ.


M Gerrits, DP Doorstam, E Spaans, R de Greef, PA Peeters and NV Organon. Effect of valproate on the glucuronidation of asenapine [abstract no. PI-68]. Clin Pharmacol Ther. 2008;83 Suppl. 1:S29.


References:

1. Asenapine (Saphrisâ) ChemIDplus. http://Chem.sis.nlm.nih.gov/chemidplus/. Accessed on November 30, 2009.


2. Saphris
â - Asenapine maleate. NDA 022117. U.S Food and Drug Administration . Center for Drug Evaluation and Research. Office of Training and Communications. Division of Informaton Services. Department of Health and Human Services. July 24, 2009. Accessed on November 17, 2009. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/.

3. Schizophrenia. NIMH National Institute of Mental Health. National Institute of Health. U.S. Department of Health and Human Services. Reviewed November 20,2009. www.nimh.nih.gov/health/topics/schizophrenia/index.shtml. Accessed November 23, 2009.

4. J Weber and PL McCormack. Asenapine. CNS Drugs. 2009;23(9):781-792.

5. Bipolar Disorder. NIMH National Institute of Mental Health. National Institute of Health. NIH Publication 08-3679. U.S. Department of Health and Human Services. Reviewed October 16, 2009. www.nimh.nih.gov/health/publications/bipolar-disorder/complete-index.shtml. Accessed November 23, 2009.

6. Schering-Plough Announces FDA Approval of Saphris
â (asenapine) for acute treatment of schizophrenia in adults and manic or mixed episodes of bipolar. Medical News Today. August 15, 2009. Accessed on November 17, 2009 at www:medicalnewstoday.com/articles/160755.php.

7. M Meltzer, A Dritselis, U Yasothan and P Kirkpatrick. Asenapine. Nature Reviews. 2009;8:843-844.

8. FDA Psychopharmacologic Drugs Advisory Committee Meeting Saphris
â (asenapine) Sublingual Tablets (NDA 22-117). July 30, 2009. Advisory Committee Briefing Materials: Available for Public Release. Schering-Plough Research Institute, A Division of Schering Corporation. Kenilworth, NJ.

9. M Shahid, GB Walker, SH Zorn and EHF Wong. Asenapine: a novel psychopharmacologic agent with a unique human receptor signature. J Psychopharm. 2009;23(1): 65-73.

10. M Gerrits, DP Doorstam, E Spaans, R de Greef, PA Peeters and NV Organon. Effect of valproate on the glucuronidation of asenapine [abstract no. PI-68]. Clin Pharmacol Ther. 2008;83 Suppl. 1:S29.

11. P Dogterom, PG Schnapbel, C Timmer, R de Greef, R Dahmen, E Spaans, PA Peeters and NV Organon. Effect of carbamazepine on asenapine pharmacokinetics [abstract no. PII-44]. Clin Pharmacol Ther. 2008;83 Suppl. 1:S55.

12. Asenapine. #832. The Merck Index, 14th ed. MJ O’Neil, ed. 2006. Merck Research Laboratories. Merck & Co., Inc. Whitehouse Station, NJ. pp.836 .


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