審議結果報告書 - pmda.go.jp

1 29 10 .. 25 mg 125 mg .. 28 10 31 .. 29 27 .. 29 7 14 .. 25 mg 125 mg .. 28 10 31 . 1 25 mg 125 mg . 1 .. C24H29N7O2.. 6- -8- -5- -2-{[5-( -1- ) -2- ] . } [2,3-d] -7(8H)- . 6-Acetyl-8-cyclopentyl-5-methyl-2-{ [5-(piperazin-1-yl)pyridin-2-yl] amino} pyrido [2,3-d]. pyrimidin-7(8H)-one .. _ _ .. 1 1 125 mg 3 . 1 1 .. 2. _ _ .. 1 . 29 6 16 .. 25 mg 125 mg .. 28 10 31 . 1 25 mg 125 mg .. 1 . 1 125 mg 3 1 . 1 .. 1.. 6. 2.. 7. 3.. 9. 4.. 15. 5.. 24. 6. 31. 7.. 44. 8.. 81. 9. 1 .. 81.. AGP 1-acid glycoprotein 1- . ALP alkaline phosphatase . ALT alanine aminotransferase . AST aspartate aminotransferase . BA bioavailability . BCRP breast cancer resistance protein . _ _.

2 BSA bovine serum albumin . BSEP bile salt export pump . CCND1 Cyclin D1 D1. CDK cyclin dependent kinase . CDKN2A cyclin-dependent kinase inhibitor 2A. 2A. CDK4/6 cyclin dependent kinase 4 and 6 4 6. CHO chinese hamster ovary . CI confidence interval . CPP critical process parameter . CQA critical quality attribute . CR complete response . CrCL creatinine clearance . CYP cytochrome P450 P450. DLT dose-limiting toxicity . DMSO dimethyl sulfoxide . E-DMC external data monitoring committee . EdU 5-ethynyl-2 -deoxyuridine 5- -2'- . ELISA enzyme-linked immunosorbent . assay ESMO 3rd ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC3). FAS full analysis set.

3 Frel relative bioavailability . FRET fluorescence resonance energy . transfer GALT gut-associated lymphoid tissue . GGT gamma-glutamyltransferase - . HBCx-34 Human breast cancer from 34 34 . patient derived xenograft . HER2 human epidermal growth factor 2 . receptor 2. hERG human ether-a-go-go related gene ether-a-go-go . HR hormone receptor .. HSA human serum albumin . ILD interstitial lung disease . IR infrared absorption spectrum . ITT intent-to-treat Ka first order rate constant of 1 . absorption KI inhibitor concentaration at 50% of 50% . maximum inhibition rate . Ki inhibition constant . kinact maximum inactivation rate constant . LC liquid chromatography.

4 LC-MS/MS liquid chromatography/tandem . mass spectrometry LH-RH luteinizing hormone-releasing . hormone MCH mean corpuscular hemoglobin . 2. _ _ . MCHC mean corpuscular hemoglobin . concentration MCV mean corpuscular volume . MedDRA Medical Dictionary for Regulatory ICH . Activities MTD maximum tolerated dose . NADPH nicotinamide adenine dinucleotide . phosphate hydrogen . NCCN National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, Breast Cancer NCI-PDQ National Cancer Institute Physician Data Query NE not estimated . NMR nuclear magnetic resonance . spectrum NZW New Zealand White . OAT organic anion transporter . OATP organic anion transporting.

5 Polypeptide OCT organic cation transporter . OS overall survival . PALOMA-1 A5481003 . PALOMA-2 A5481008 . PALOMA-3 A5481023 . PAR proven acceptable range . Papp A B apparent permeability in apical to . basolateral direction . Papp B A apparent permeability in basolateral . to apical direction . P-gp P-glycoprotein P- . PD progressive disease . PFS progression free survival . PF-05089326 . PK pharmacokinetics . PPI proton pump inhibitors . PPK population pharmacokinetics . PR partial response . PT preferred term . PTP press through packaging / . / 3 .. QbD quality by design . QD quaque die 1 1 . QTcS QT .. Q4W quaque 4 weeks 4 . Rb Retinoblastoma . Rb S780 Rb 780.

6 Rb S795 Rb 795 . 3. _ _ . Rb S807/811 Rb 807/811 . RECIST Response Evaluation Criteria in . Solid Tumors . SA- -gal senescence associated - - - . galactosidase SCID severe combined immunodeficient . mouse SD stable disease . SMQ standardised MedDRA queries SOC system organ class . SULT Sulfotransferase . tlag lag time for absorption . UGT uridine diphosphate glucuronosyl . transferase UV/VIS ultraviolet/visible spectrum . V2/F apparent volume of distribution of . central compartment 01 A5481001 . 02 A5481002 . 04 A5481004 . 09 A5481009 . 10 A5481010 . 11 A5481011 . 12 A5481012 . 13 A5481013 . 14 A5481014 . 15 A5481015 . 16 A5481016 . 17 A5481017 . 18 A5481018.

7 20 A5481020 . 21 A5481021 . 22 A5481022 . 26 A5481026 . 32 A5481032 . 36 A5481036 . 38 A5481038 . 39 A5481039 . 40 A5481040 . 14 14. C C .. 2015 .. / . / .. 4. _ _ . / . / .. / . / . / .. / .. / . / .. / .. 5. _ _ . 1.. 80% CDK4 D CDK4/6. p16 CDK4/6 . Cancer Cell 2002; 2: 103-12 . Warner-Lambert Pfizer CDK4/6 . CDK4/6 D Rb .. Pfizer 2004 9 . 01 2008 9 HR HER2 . / / PALOMA-1 2013 2 . 2013 9 . HR HER2 . / PALOMA-2 . HR HER2 . / PALOMA-3 . PALOMA-1 2014 8 / . 2015 2 IBRANCE is indicated in combination with letrozole for the treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.

8 PALOMA-2 . PALOMA-3 2015 10 / . 2016 2 IBRANCE is indicated for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in combination with fulvestrant in women with disease progression following endocrine therapy. PALOMA-2 . 2016 10 / 2017 3 . IBRANCE is indicated for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women or fulvestrant in women with disease progression following endocrine therapy. EU . PALOMA-1 PALOMA-3 2015 8 . 2016 11 IBRANCE is indicated for the treatment of HR-positive, HER2-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or in combination with fulvestrant in women who have received prior endocrine therapy.

9 2017 4 33 .. HR HER2 . / 10 2012 10 PALOMA-2 . 6. _ _ . PALOMA-3 20 20 . PALOMA-2 PALOMA-3 . 2.. 2 Form A B 1 Form C . Form . Form . UV/VIS IR NMR 1H- 13C-NMR X .. 1 2 .. QbD . CQA PF-004478803 PF-007100424 PF-066514645 PF-003108646 .. CQA CPP . PAR . CQA . 7 .. IR . LC . LC LC .. 1 . 1 . 2 . 3 . 4 . 5 . 6 . 7 . 7. _ _ . 1 .. 25 60%RH 36 . 3 40 75%RH 6 .. 1 25 125 mg .. QbD . CQA PF-066948078 .. CQA CPP . PAR . CQA .. LC . LC . LC .. 2 . 2 .. 25 60%RH 18 . 25 mg 40 75%RH 6 . PTP . 3 25 60%RH 36 . 125 mg 40 75%RH 6 . 8 . 8. _ _ . 25 mg PTP 18 . 125 mg PTP 36 . 25 mg 36 .. 3.. CDK CTD . CDK . 32P IC50 1 nmol/L 3.. PF-05089326 . CDK4 CDK6 IC50 n 1 nmol/L . 3 CDK.

10 N IC50 nmol/L . CDK4/ D1 3 2 CDK4/ D3. 1 CDK6/ D2 2 CDK6/ D3 1 CDK9/ T1 1 n 1 2 . CTD . 274 . 1 mol/L 70% IC50 . 4 . 4 . IC50 nmol/L IC50 nmol/L . CLK1 32 CLK2 352. HIPK2 139 PKD3 408. MAP2K5 180 PKD2 555. FLT3 106 PKR 482. ERK5 259 DYRK1B 323. n 1 . 174 FRET . 75% CLK1 CLK2 IC50 n 1 373 . 193 nmol/L . 9. _ _ . Rb CTD . MCF7 T47D 9 MDA-MB-435 . Rb ELISA . Rb S780 Rb S795 Rb S807/811 IC50 5 .. 5 Rb . IC50 nmol/L .. Rb S780 Rb S795 Rb S807/811. MCF7 T47D 5. MDA-MB-435 66 63 . n 1 n 1 3 . T47D MCF7-CYP19 . Rb E2F1 . FoxM1 c-Myc . Rb E2F1 FoxM1. c-Myc . MDA-MB-435 Colo205 SCID 2 / . 3 / 150 mg/kg Rb S780 . MDA-MB-435 . SCID 75 150 mg/kg Colo205 SCID 3 /. 90% Rb S780.