平成 28 30 - pmda.go.jp

1 29 17 .. 28 30 .. 29 .. 29 1 18 .. mg .. 28 3 30 . 1 mg . 1 .. C32H34N4O6 C7H8O3S.. (5R)-17-( )-6,7- -4,5- -3,6,14- -N- [2-(3- -1,2,4- -5- ) -2- ] -7- . (4- ).. (5R)-17-(cyclopropylmethyl)-6,7-didehydr o-4,5-epoxy-3,6,14-trihydroxy-N-[2-(3-ph enyl-1,2,4- oxadiazol-5-yl)propan-2-yl]morphinan-7-c arboxamide mono(4-methylbenzenesulfonate).. 1 mg 1 1 .. 2.. 1 . 28 11 30 .. mg .. 28 3 30 . 1 mg .. 1 mg 1 1 .. 1. 1.. 4. 2.. 4. 3.. 6. 4.. 11. 5.. 15. 6.. 21. 7.. 35. 8.. 59. 9. 1 .. 59.. ALP Alkaline phosphatase . ALT Alanine aminotransferase . AST Aspartate aminotransferase . AUC Area under concentration-time curve . AUC0-24h Area under concentration-time curve 0 24 . up to 24 hours AUC0- Area under concentration-time curve . during dose interval.

2 AUC0-inf Area under concentration-time curve 0 . up to infinity BA Bioavailability . BCRP Breast cancer resistance protein . BPI Brief pain inventory . A* . BSS Bristol stool form scale . CMA Critical material attribute . Cmax Maximum plasma concentration . COWS Clinical Opioid Withdrawal Scale . CPK Creatine phosphokinase . CPP Critical process parameter . CQA Critical quality attribute . CSBM Complete spontaneous bowel . movement CYP Cytochrome P450 P450. DAMGO D-Ala2, N-Me-Phe4, Gly5-ol - . enkephalin B* . ED50 50 % effective dose 50 % . FAS Full analysis set . Feu Fraction of dose excreted into the . urine FOB Functional observational battery . GC Gas chromatography . GGT Gamma-glutamyl transferase - . hERG Human ether- -go-go related gene ether-a-go-go.

3 HPLC High performance liquid . chromatography ICH International conference on EU . harmonization of technical requirements for registration of pharmaceuticals for human use ICH Q1E . 15 6 3 . 0603004 . C* . IR Infrared absorption spectrum . Kb Binding constant . Ki Inhibition constant . Kobs Observed association rate constant . Koff Dissociation rate constant . LC/MS/MS Liquid chromatography tandem mass . spectrometry . MACE Major adverse cardiac events . MedDRA/J Medical Dictionary for Regulatory ICH . Activities Japanese version MS Mass spectrum . NMR Nuclear magnetic resonance spectrum . NRS Numerical rating scale . OAT Organic anion transporter . OATP Organic anion transporting . polypeptide 2 * . OCT Organic cation transporter . OIC Opioid-induced constipation.

4 PAC-QOL Patient assessment of constipation- QOL . Quality of life PAC-SYM Patient assessment of constipation . symptoms . P-gp P-glycoprotein P- . PPS Per protocol set . PS Performance status . PTP Press through package . QbD Quality by design . QTc Corrected QT interval QT . QTcF Fridericia-corrected QT interval Fridericia QT . RH Relative humidity . SBM Spontaneous bowel movement 24 .. t1/2 Elimination half-life . tmax Time to reach maximum plasma . concentration UGT Uridine diphospho-glucuronosyl . transferase UV Ultraviolet-visible absorption . spectrum U-50488H trans-3,4-dichloro-N-methyl- . N[2(pyrrolidinyl)-cyclohexyl]- benzeneacetamide WBP Whole body plethysmography . QTcF QTcF .. 2012 3 .. 2014 . 2014 . 2014 5 .. 3-G Naldemedine 3-O- -D-glucuronide 3-O- -D.

5 6-G Naldemedine 6-O- -D-glucuronide 6-O- -D- . -CA Naldemedine-carboxylic acid .. 2012 7 .. 3. 1.. Opioid- induced constipation OIC Drugs 72: 1847-1865, 2012 OIC . OIC . J Med Econ 16: 1423-1433, 2013 Pain 112: 372-380, 2004 . OIC .. 2014 .. OIC . 2016 11 . 2.. pH . I .. MS IR UV NMR 1H-NMR 13C-NMR .. QbD . CQA . p- . CPP .. UV IR HPLC . GC HPLC . 4.. 1 .. 1 .. 30 65%RH 36 . 3 40 75%RH 6 .. 1 mg mg . D- . * .. QbD . CQA CMA CPP . CQA .. HPLC/UV HPLC . HPLC HPLC .. 2 .. 2 .. 25 60 %RH 24 . PTP+ . 3 40 75 %RH 6 . ICH Q1E PTP . 36 .. 5 * .. 3.. % .. CTD 02 . R-297995-EB-074-N S-297995-EF-284-N . CKO-K1 .. Ki nmol/L . 50 % Kb . nmol/L .. DAMGO Met5 -enkephalin U-50488H . CTD 06 12 S-297995-EB-224- N S-297995-EB-222-N R-297995-EB-311-R . Kobs.

6 Min-1 Koff min-1 .. CTD . 09 R-297995-EB-071-N S-297995-EB-221-N . 10 mg/kg 15 3. mg/kg 30 % 15 . 1) 3 10 mg/kg . 1).. 100 % . 6. ED50 mg/kg . 3 3 mg/kg .. % . *. **.. **. mg/kg . 1 **. 3 **. 10 **. n=10. * p< ** p< vs. Dunnett's . 10 mg/kg 15 . 20 mg/kg 30 % . 15 1) 4 10. mg/kg ED50. mg/kg . 4 20 mg/kg .. % . **.. **. mg/kg . 1 **. 3 **. 10 **. n=12. ** p< vs. Dunnett's . CTD . R-297995-EB-092-N . 1 mg/kg 45 . 15 1 mg/kg 1 . 0 1 . 2 5 . 1 mg/kg . ED50 mg/kg . 7. 5 1 mg/kg . % .. 1 2 . 0 0 0. 0 0 0. 18 27 45. 18 82 100**. mg/kg 0 100 100**. 0 100 100**. 1 0 100 100**. n=11. ** p< vs. Steel . CTD . S-297995-EF-260-N . 3 mg/kg 30 . 1 mg/kg 15 % . 15 1) 6 3. mg/kg . ED50 mg/kg . 6 1 mg/kg .. % . **. mg/kg **. **. 1 **. 3 **. n=10. ** p< vs.

7 Dunnett's .. CTD R-297995-EF-081-N . 62 10 mol/L . 50 % . CTD R-297995-EF-284-N S-297995- EB-135-N . 5 nor- 3-G 6-G . -CA Ki Kb 7 8 .. 8. 7 Ki . Ki nmol/L .. nor- 61 13. 3-G 915 320. 6-G 36 8. -CA 151 33. >2,644 >2,943 >6,250.. 8 Kb . Kb nmol/L .. nor- > 3-G > > 6-G -CA 201 ND a) ND a) > . a . CTD 03 04 R-297995-EB-072-N . S-297995-EB-181-N S-297995-EB-274-N . 1 3 10 30 mg/kg 1 . 6 mg/kg 45 .. 3 5 7 10 30 mg/kg 24 . 6 mg/kg . 45 10 mg/kg 6 30 mg/kg 4 . 6 8 . 1 3 5 7 mg/kg 8 .. 6 mg/kg 45 5 mg/kg 6 7 mg/kg 4 . 6 8 .. 9 . 9. 9 . CTD.. 30, 100, 300. FOB 300 mg/kg R-297995- 6 mg/kg SF-075-L . WBP 1 30, 100, 300. 300 mg/kg R-297995- 8 mg/kg SF-077-L . 100. mg/kg 30 mg/kg 4 10, 30, 100. 4 1 100 mg/kg R-297995- mg/kg 1 4 SF-076-L .. 30 mol/L APD90 APD30-90 , 3, 30.

8 APD in vitro APD90 APD30 10 % R-297995- mol/L. 5 1 SF-078-L . 3 30 mol/L HEK293 , 3, 30. hERG in vitro % % % IC50 R-297995- 5 mol/L. 30 mol/L SF-079-L .. Drugs 72: 1847-1865, 2012 .. 7 mg/kg . 3 mg/kg . 3 mg/kg Cmax 282 45 ng/mL . 2) mg/ Cmax ng/mL ng/mL .. 2). II V9222 .. II V9221 . 10.. 4.. 14. C . nor- 3-G 3) . LC/MS/MS . ng/mL CTD ng/mL. CTD nor- 3-G ng/mL CTD 06 ng/mL CTD ng/mL CTD nor- 3-G ng/mL . ng/mL CTD 14C .. CTD 11 R-297995-PB-070-N . S-297995-PB-161-N .. 10 11 AUC0-inf . Cmax 3 mg/kg . 10 . Cmax tmax AUC0-inf t1/2 BAa .. mg/kg ng/mL h ng h/mL h % . 19 5 68 24 1 38 3 172 33 . 3 168 48 674 166 10 853 175 2,650 220 351 29 .. 1 725 61 . n=4 . a mg/kg AUC0-inf . 3). nor- 3- G .. 11. 11 . Cmax tmax AUC0-inf t1/2 BAa .. mg/kg ng/mL h ng h/mL h %.

9 58 36 291 45 1 213 81 989 127 . 3 963 346 3,700 500 10 4,110 630 19,500 2,800 989 72 .. 1 1,970 190 . n=4 . a mg/kg AUC0-inf . CTD S-297995-PF-197-N .. 12 . 12 . Cmax tmax AUC0-24h Cmax tmax AUC0-24h . mg/kg ng/mL h ng h/mL mg/kg ng/mL h ng h/mL . 270 36 697 214 2,460 330. nor- . 179 37. 1 7.. 3-G. 282 45 1,110 330 915 90 4,000 930. nor- . 249 60. 3 10.. 3-G. 518 73 1,940 350 3,260 720 15,700 2,900. nor- . 146 28 193 26 1,050 90. 5 30.. 228 40. 3-G. n=4 . CTD 06 R-297995-TB-046-L S-297995-TF-219-L . 30 9 . 1 1 30 9 . 13 14 AUC0- 24h Cmax 30 1 3 mg/kg/ . 3 50 mg/kg/ 9 1 4 mg/kg/. 4 20 mg/kg/ . AUC0-24h Cmax . 12. 13 30 .. Cmax AUC0-24h Cmax AUC0-24h mg/kg/ . g/mL g h/mL g/mL g h/mL . 1 . 30 nor- 1 NC NC NC NC. 1. 30 NC NC NC NC. 1 NC NC NC NC.

10 3-G 30 NC NC NC NC. 1 . 30 nor- 1 3. 30 1 NC NC NC NC. 3-G 30 NC NC NC NC. 1 . 30 nor- 1 10. 30 1 NC NC 3-G 30 1 . 30 nor- 1 50. 30 1 3-G 30 n=3 50 mg/kg n=5 NC g/mL . 14 9 .. Cmax AUC0-24h Cmax AUC0-24h mg/kg/ . g/mL g h/mL g/mL g h/mL . 1 . 273 1. 1 273 1 . 273 4. 1 273 1 . 273 20. 1 273 n=4.. CTD 04 R-297995-PB-057-N S-297995-PF-213- N . 1 14C 1 mg/kg 1 4 . 8 24 72 4) . 1 1 .. 4).. 13. 8 .. 14C 1 mg/kg .. CTD S-297995-PF-238-N . 14C 1 mg/kg 18 . 1 2 .. 24 .. CTD 02 R-297995-PB-025-N. R-297995-PB-098-N . 14C 2 1 mg/kg . 15 . 15 14C 1 mg/kg . % % . [oxadiazole-14C]- 5 168 [carbonyl-14C]- 4 168 . 14C 2 1 mg/kg . 16 . 16 14C 1 mg/kg . % % % . [oxadiazole-14C]- 4 48 [carbonyl-14C]- 5 48 . [oxadiazole-14C]- . [carbonyl-14C]- . [oxadiazole-14C].