1

19 2554

. 49210738 . 50210300 . 50210553 . 50234597

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Asenapine : Asenapine (1) : Saphris ( Schering-Plough Corporation) (2) : (3aRS,12bRS)-5-Chloro-2-methyl-2,3,3-a,12b-tetrahydro-1H dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole(2Z)-2-butenedioate ( 1) (2) : C17H16ClNOC4H4O4 401.84 (2) : atypical antipsychotic drugs (3) : Asenapine atypical antipsychotic drugs positive symptom , negative symptom cognitive impairment blood brain barrier serotonin receptor antagonist 5-HT2A receptor prefrontal , 5-HT2C receptor nucleus accumbens striatum , 5-HT6 receptor medial prefrontal cortex, 5-HT7 receptor cortico-limbic areas 2-adrenergic receptor prefrontal dopamine negative symptom dopamine receptor antagonist postsynaptic dopamine D2 receptor mesolimbic frontal cortex postsynaptic dopamine D3 receptors medial thalamus dopamine positive symptom (1,4) : ( 2009) (1) : 5 mg (1) : 5 mg 2 (5) : (Schizophrenia) 3

1) 2) prefrontal cortex

temperal cortex 3) 3

3.1) Dopamine dopamine prefrontal cortex positive symptom 3.2) Serotonin serotonin mesocortical dopamine receptors

dopamine negative symptom 3.3) Glutamate glutamate prefrontal cortex negative symptom 2 1). (typical antipsychotic drugs)

Haloperidol 2). (atypical antipsychotic drugs) Clozapine

1 Asenapine (2)

2

1 (1,4) 1 Asenapine sublingual tablets 5 mg

: *UGT1A4 : uridine diphosphate-glucuronyltransferase 1A4

2 (6) 2 Asenapine Haloperidol

Efficacy and safety of asenapine in a placebo- and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia

Kane JM, Cohen M, Zhao J, Alphs L, Panagides J. Asenapine schizophrenia

haloperidol active control Multicenter Randomized, Double-blind, Placebo-Controlled Trial 48 centers 17 centers, 11 centers, 7 centers,

7 centers, 1 center 2005 2006 513 458

fixed-dose 6 ( 2 ) - 114 asenapine 5 mg 2 - 106 asenapine 10 mg 2 ( asenapine 5 mg 2

asenapine 10 mg 2 ) - 115 haloperidol 4 mg 2 - 123

- 18 schizophrenia - 60 positive and negative symptom scale total score (PANSS) - 4 Clinical Global Impression-Severity of Illness (CGI-S)

-, residual-type schizophrenia, schizoaffective disorder, coexisting psychiatric disorder - - 20% positive negative symptom scale total score (PANSS) - haloperidol

458 Efficacy Assessments

- Primary efficacy ; PANSS , 4 - Secondary efficacy ; PANSS subscale Safety and Tolerability Assessments - Vital sign, , , 2, 3, 4 6 - Extrapyramidal symptom SAS*, BARSS*, AIMS* - Movement disorders

Bioavailability Metabolism Half-life Distribution Protein Binding Time to peak Elimination Clearance

35% *UGT1A4, CYP1A2 (major) CYP3A4, CYP2D6 (minor)

24

20-25 L/kg 95%

0.5 1.5

~ 90% - (50%) - (40%)

52 L/hr

; SAS*: Simpson-Angus Scale , BARSS*: Barnes Akathisia Rating Scale, AIMS* : Abnormal Involuntary Movement Scale

3

Efficacy Assessment : *MMRM analysis PANSS score Primary efficacy ; PANSS total score - PANSS total score - MMRM asenapine 5 mg BID haloperidol PANSS total score 21 asenapine 10 mg BID PANSS total score 42 asenapine 5 mg BID asenapine 10 mg BID Secondary efficacy 1.PANSS Positive Subscale Score - MMRM asenapine 5 mg BID haloperidol PANSS Positive Subscale Score 21 asenapine 10 mg BID 42 asenapine 5 mg BID asenapine 10 mg BID 2. PANSS Negative Subscale Score - MMRM asenapine 5 mg BID PANSS Negative Subscale Score 35 42 3. PANSS General Psychopathology Subscale Score - MMRM asenapine 5 mg BID PANSS General Psychopathology Subscale Score 21 haloperidol 21 asenapine 10 mg BID Safety and Tolerability Assessments : - Extrapyramidal Symptoms (EPS) - EPS asenapine 5 mg BID, asenapine 10 mg BID, , haloperidol 15%,18%, 10%,34% asenapine 5 ,10 mg BID EPS haloperidol

PANSS MMRM 6 asenapine 5 mg BID acute schizophrenia 21 asenapine 10 mg BID acute schizophrenia 42 asenapine 5 mg BID 10 mg BID Extrapyramidal Symptoms haloperidol

; *MMRM analysis; mixed model for repeated measures

(6) : 1.1 positive and negative symptom 2

- Primary outcome ; PANSS total score - Secondary outcome ; PANSS subscale score, PANSS general psychopathology subscale score, PANSS Marder factor scores,

CGI-Severity of Illness scale, CDSS, PANSS response rate, CGI- Improvement Scale, response rate 1.2 Extrapyramidal Symptoms Laboratory Measures (6) : Extrapyramidal Symptoms 15%, 20%, 9%, 5% (7) : 1. asenapine fluvoxamine CYP1A2 inhibitor asenapine 29% asenapine 2. asenapine weak inhibitor CYP2D6 paroxetine ( CYP2D6 substrate) paroxetine asenapine paroxetine (4) : 1. cardiovascular events

2. , (orthostatic hypotension)

: (4) : 400 mg

4

(4) : 1.

2.

(3, 6, 8) Asenapine Haloperidol atypical antipsychotic serotonin receptor antagonist

5-HT2A , 5-HT2C , 5-HT6 , 5-HT7 receptor 2-adrenergic receptor dopamine receptor antagonist D2 D3 receptors

typical antipsychotic dopamine D2 antagonist

Saphris Haldol acute schizophrenia acute and chronic schizophrenia sublingual 5 mg 2 0.5-5 mg 2-3 Sublinguals Tablets Extrapyramidal Symptoms 15%, 20%,

9%, 5% Extrapyramidal Symptoms 34%, 14%, 15%, 9%,

Bioavailability (%) 35 60 Protein binding (%) 95 90 Volume of Distribution 20-25 L/kg 8-18 L/kg Metabolism UGT1A4, CYP1A2 (major) CYP3A4, CYP2D6 (minor) CYP2D6 Half life (hours) 24 18 Excretion (50%), (40%) (33%-40%), (15%) CL 52 L/hr 33 L/hr Pregnancy category C C

Asenapine atypical antipsychotic 5-HT2A ,5-HT2C ,5-HT6 5-HT7 receptor negative symptom postsynaptic dopamine D2 D3 receptor positive symptom Asenapine 5 mg 2 Extrapyramidal Symptoms Haloperidol 1. Schering-Plough research institute; Advisory committee briefing materials, Division of Schering corporation. FDA psychopharmacologic d rugs advisory

committee meeting, Saphris

(asenapine) sublingual tablets (NDA 22-117). New jersey (USA): Schering-Plough research institute; 2009. 2. Meltzer HY, Dritselis A, Yasothan U, Kirkpatrick P. Fresh from the pipeline Asenapine. Nat Rev Drug Discov. 2009; 8: 843-4. 3. Frnberg O, Marcus MM, Ivanov V, Schilstrm B, Shahid M, Svensson TH. Asenapine elevates cortical dopamine, noradrenaline and serotonin release.

Evidence for activation of cortical and subcortical dopamine systems by different mechanisms. J Clin Psychopharmacol. 2009; 204: 251-264. 4. Asenapine [homepage on the Internet]. Thompson micromedex (Healthcare series). Greenwood Village, Colorado. c2010 [updated 2010 Oct 7; cited 2010

Nov 6]. Available from: http://www.thomsonhc.com 5. Hales RE, Yudofsky SC, Gabbard GO, editors. The American psychiatric publishing textbook of psychiatry. 15th ed. United State: American psychiatric

publishing. 2008: 426-33. 6. Kane MJ, Cohen M, Zhao J, Alphs L, Panagides J. Efficacy and safety of asenapine in a placebo and haloperidol-controlled trial in patients with acute

exacerbation of schizophrenia. J Clin Psychopharmacol. 2010; 30(5): 106-15. 7. Weber J, McCormack LP. Asenapine. CNS Drugs. 2009; 23(9): 781-92. 8. Lacy CF, Armstrong LL, Goldman MP, Lance LL, editors. Drug information handbook. 19th ed. United State: Lexi-Comp; 2010-2011: 787-9.