部（モジュール 2）：CTD の概要（サマリー）

1 1 1 mg 2 mg 2 2 CTD 2 .. 2 .. 6 .. 10 .. 10 .. 10 .. 10 .. 11 .. 12 .. 12 .. 13 .. 14 .. 16 .. 19 .. 19 .. 20 .. 20 .. 21 .. 23 .. 23 .. 23 .. 23 .. 24 .. 24 .. 24 .. 25 .. 25 .. 25 CYP2D6 .. 25 .. 26 .. 26 .. 26 .. 26 3 .. 26 .. 28 .. 28 QTc .. 28 .. 29 .. 30 .. 30 .. 31 331-10-002 331-10-230 331-10-231.

2 31 331-10-003 .. 33 331-10-232 .. 33 .. 33 331-10-002 331-10-230 331-10-231 .. 34 331-10-003 .. 37 331-10-232 .. 37 .. 38 .. 39 .. 39 .. 39 .. 42 .. 42 .. 43 .. 45 .. 45 .. 45 .. 46 .. 48 .. 48 .. 48 .. 49 .. 50 .. 50 4 .. 51 .. 52 .. 53 .. 53 .. 54 .. 54 .. 56 .. 56 CPK .. 57 .. 58 .. 59 .. 59 .. 60 .. 60 .. 61 .. 61.

3 62 .. 64 .. 64 QT .. 65 .. 66 .. 66 .. 66 .. 67 .. 67 .. 67 .. 67 .. 68 .. 68 .. 68 .. 68 .. 69 .. 69 .. 69 .. 69 5 .. 70 .. 70 .. 70 .. 71 .. 73 .. 73 .. 74 .. 76 .. 78 6 5-HT1A 5-hydroxytryptamine 1A 5-HT1A 5-HT2A 5-hydroxytryptamine 2A 5-HT2A AIMS abnormal involuntary movements scale AUC area under the concentration-time curve AUC area under the concentration-time curve from time zero to infinity 0 AUC ,u unbound area under the concentration-time curve from time zero to infinity 0 AUCt,u unbound area under the concentration-time curve calculated to the last observable concentration at time t 0 AUC area under the concentration-time curve during the dosing interval at steady state ( )

4 BA bioavailability BARS Barnes akathisia rating scale Barnes BE bioequivalence BCRP breast cancer resistance protein BMI body mass index BPRS brief psychiatric rating scale BSEP bile salt export pump CGI-I clinical global impression - global improvement CGI-S clinical global impression - severity of illness CI confidence interval CL/F apparent clearance of drug from plasma after extravascular administration CLcr creatinine clearance CLu/F apparent unbound clearance of drug from plasma after extravascular administration Cmax maximum (peak) plasma concentration of the drug Cmax,u unbound maximum (peak) plasma concentration of the drug CMH Cochran-Mantel-Haenszel C-SSRS Columbia suicide severity rating scale CYP cytochrome P450 P450 D2/D3 dopamine D2/ dopamine D3 D2/D3 7 DIEPSS drug induced extra-pyramidal symptoms scale DOI ( )

5 -2,5-dimethoxy-4-iodoamphetamine DSM-IV-TR diagnostic and statistical manual of mental disorders, fourth edition, text revision 4 EM extensive metabolizer EPS extrapyramidal syndrome EU European Union F absolute bioavailability FDA Food and Drug Administration FMO flavin-containing monooxygenase GAF global assessment of functioning scale [I] inhibitor concentration IC50 concentration of drug producing 50% inhibition 50% IM intermediate metabolizer ISS integrated summary of safety Ki inhibition constant LOCF last observation carried forward MATE1 multidrug and toxin extrusion 1 MATE2-K multidrug and toxin extrusion protein 2 MedDRA medical dictionary for regulatory activities ICH MDR1 multidrug resistance 1 1 MMRM mixed model repeated measures OAT organic anion transporter 1 OATP organic anion transporting polypeptide OC observed case OCT organic cation transporter OPDC Otsuka Pharmaceutical Development & Commercialization, Inc.

6 PANSS positive and negative syndrome scale PEC PANSS excited component PET positron emission tomography PM poor metabolizer PSP personal and social performance scale QOL quality of life QTc corrected QT interval QT 8 QTcB QT interval as corrected by Bazett s formula Bazett QT QTcF QT interval as corrected by Fridericia s formula Fridericia QT QTcI individually corrected QT interval QT SAS Simpson-Angus scale SCI-PANSS structured clinical interview for PANSS SDAM serotonin dopamine activity modulator TDI time-dependent inhibition tmax time to maximum (peak) plasma concentration Vc/F apparent volume of the central compartment 9 JAN OPC-34712 (OPC-331 Lu AF41156)

7 DM-3411 Lu AF59163 -3,4- -3,4- DM-3412 -3,4- -3,4- DM-3413 7- DM-3404 - OPC-3952 -1- OPC-34835 FRE OPC-54050 - MOP-54522 SFO-34318 MOP-34318 FRE 10 2011 22 23 1 2 3 4

8 D2 5 5-HT2A Meltzer 6 D2 EPS 7 1950 8,9,10,11,12 13 14 EPS EPS 11 EPS 15 16 26 60 50% 50% 17 QOL 18 19 Byerly

9 57% 20 21 22 23,24,25,26 1 27 QOL QOL 28 20 SDAM D2 5-HT1A 5-HT2A - 1B 2C D2 12

10 In vivo DOI 5-HT2A D2 EPS 5-HT1A 5-HT2A D2 EPS 7 EPS D2 1A H1 D2 H1 H1 EPS QOL 20 15 5 5 5 I 331-08-205 II 13 331-07-203 III 331-10-230 331-10-231 III 331-10-231 331-10-232 14644A 331-10-232 II 331-07-203 331-08-210 III