2012 4 5 873112 2008 () 1 0.5g 0.5g 0.75g 0.75g JAN EldecalcitolJAN 2011 1 21 2011 3 11 2011 4 11 TEL0120-591-818 03-3985-5599 8:3017:00 http://www.taishotoyama.co.jp/ 20124 http://www.info.pmda.go.jp/
IF 63 10 9 10 20 9 2
2008 2008 2008 21 4 2008 2008 2008 9
... 1... 1... 1... 2... 2... 2... 2... 2... 2... 2... 2... 3... 3... 3... 3... 3... 4... 4... 4... 4... 5... 5... 5... 5... 5... 5 10... 5 11... 5 12... 5 13... 6 14... 6... 7... 7... 7... 7... 12.. 12... 12... 17... 17... 19... 20... 20... 21... 22... 23... 24... 24.. 24... 24... 24... 24... 25... 25... 26... 29 10... 29 11... 29 12... 29 13... 29 14... 29 15... 30 16... 30... 31... 31... 31... 34... 34... 34
... 34... 34... 34... 34... 34... 34... 34 10... 35 11... 35 12... 35 13... 35 14... 35 15... 35 16... 35 17... 35... 36... 36... 36... 37... 37... 37... 38
0.5g 0.75g D3 1) 腿 ADL QOL D3 D3 D3 2 D3 D33 腿 2011 1 21 D3VI2 VI2 V3(5) V3(5) 802 309 38.5% 456 163 20.3% 120 15.0% 15 1.9% 12 1.5% 1) 10.4mg/dL 11.0mg/dL 2) 11.0mg/dL 1
0.5g 0.75g EDIROL Capsule 0.5g EDIROL Capsule 0.75g Effective Vitamin DInnovative D3ROL D3 JAN EldecalcitolJANeldecalcitolr-INN D /-calci- H H 3 C CH 3 H H 3 C OH CH 3 H CH 2 HO H O H OH H HO C30H50O5 490.72 (1R,2R,3R,5Z,7E)-2-(3-Hydroxypropyloxy)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triolIUPAC ED-71 104121-92-8 2
N,N-99.5 132 C 20 D 38.0 40.0 40 mg99.510 ml100 mm 20 C 36 5 C 6 60 C70 C80 C ) 4 607080 70 C80 C 50 C 75%RH () 3 120 lx hr 437 W h/m 2 3
0.5g 0.75g 6.6mm 164mg 0.5g 0.75g 0.5g 0.75g PTP 0.5g 0.75g 1 0.5g 0.5g 0.75g 0.75g 0.5g D- 0.75g D- 4
25 C 60%RH PTP/ 36 30 C 65%RH PTP/ 12 40 C 75%RH PTP/ 6 60 C 2 50 C 75%RH () 4 120 lx hr 499 W h/m 2 (1R,2R,3R,6E)-2-(3-Hydroxypropyloxy)-9,10-secocholesta-5(10),6,8(9)-triene-1,3,25-triol (1R,2R,3R,5E,7E)-2-(3-Hydroxypropyloxy)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol 5
6
1. 2. 2. 20 1 1 0.75g 1 1 0.5g 1 1 0.5g 1 1 0.5g 1 1 0.75g D3 36 1 VIII.-8.(2) (6LI2) (ED-110JP) (ED-112JP) (ED-113JP) (ED005JP) (ED006JP) 2 7
(6CI2) (ED-71T-103) (ED-301JP) (ED-111JP) CYP3A4 (ED008JP) (ED-71T-201) (ED007JP) (ED-209JP) 1,054 528 526 3 1 1 0.75g 13.4%1 1 1.0g 17.5% 26% log-rank P=0.04603 1.1% 3.6% 71% log-rank P=0.00483 1 1 0.75g 3.4%1 1 1.0g 0.1% Student t P<0.0013 腿 0.4%2.3% Student t P<0.001 3 13.4% 17.5% 1.1% 3.6% 1Kaplan-Meier 2 log-rank P 26% P=0.0460 71% P=0.0048 2) 51 0.011.0g 8
1.0g 3) 40 0.11.0g 15 1.0g 4) 15 110.75g 110.5g 1996 4 0.25g0.5g0.75g1.0g2411 D 0.25g280.5g28 0.75g261.0g 26 L2-4BMD sca uca sp1,25(oh)2d24,25(oh)2d25(oh)dintact-pth 2 4L2-4BMD 0.75g 0.25g 28517.9%50.5g 28414.3%7 0.75g 26415.4%71.0g 261038.5%18 0.25g 0.5g 0.75g 13.8%21.0g 623.1%7 1.0g 1.0g 0.51.0g 110.75g 5) 110.75g 110.5g 2000 DXA L2-4BMDHologic QDR L2-4BMD 0.708g/cm 2 9
2-4 L2-4BMD 0.809g/cm 2 3 3 0.5g0.75g1.0g4811 D 25(OH)D 20ng/mL D 400IU20ng/mL 200IU 0.5g550.75g55 1.0g5653 L2-4BMD Total hip BMD sca uca sp1,25(oh)2d24,25(oh)2d25(oh)dintact-pth 48 L2-4BMD MeanSD 0.723.99%0.5g 2.164.02%0.75g 2.643.64%1.0g 3.193.57%0.5g 48 腿 Total hip BMD MeanSD0.883.45%0.5g 0.784.12%0.75 g 0.623.60%1.0g 0.913.33% 0.75g 53815.1%90.5g 551730.9% 280.75g 551527.3%281.0g 562748.2% 43 1.0g 110.75g 6) 110.75g 110.5g ALF ALF 2000 70 YAM 60% 3 0.75g ALF 1.0g 144311 0.5g ALF 0.5g25(OH)D 20ng/mL D 400IU 0.75g528ALF 1.0g526 L2-4BMDTotal hip BMD sca uca 1,25(OH)2D24,25(OH)2D25(OH)Dintact-PTHCT QOL 31 10.75g13.4%ALF 111.0g17.5% 26% log-rank P=0.04603 1.1%ALF 3.6%71% 10
V.-3.(5)2) log-rank P=0.00483 L2-4BMD 110.75g3.4%ALF 111.0g0.1% ALF Student t P<0.001 3 Total hip BMD 0.4%ALF 2.3%Student t P<0.001 52822743.0%320ALF 526 17032.3%208 2) ED-71T-201ED007JPED-209JP 20 0.75g 2 9 11 L2-4BMD Total hip BMD 9 1 20 18 90% 94 3 15%782 736 94.1% 4058 236 30.2% 7) 11
D D3 1,25(OH)2D3 D3 Ca 1,25(OH) 2 D 3 Ca VDR VDR D3 1in vitro 8) rhm-csf33ng/ml Receptor activator of nuclear factor kappa B srankl100ng/ml 0.1110100nmol/L 10 100nmol/L (mol/l) 12 mean + SE (n = 6) # P < 0.05 vs rhm-csf unpaired t-test * P < 0.05 vs rhm-csfsrankl Dunnett s multiple range test
2 Ca 9) 0.10.31g/kg 1,25(OH)2D31g/kg 6 Ca Ca 1g/kg 1,25(OH)2D3 Ca meansd (n = 4) * P < 0.05 vs Vehicle Dunnett s multiple range test 3 Ca Ca 10) 0.0050.010.0250.050.1g/kg/ 12 Ca Ca 0.1g/kg 2 Ca Cavehicle 0.050.025g/kg 12 Ca Ca 0.01g/kg 12 Ca Ca 0.005 g/kg 2 12 Ca Ca 12 Ca Ca Vehiclen=80.005μg/kgn=80.01μg/kgn=780.025μg/kgn=78 0.05μg/kgn=78 0.1μg/kgn=8 meanse * P < 0.05212 vehicle 0 Dunnett-Hsu 13
4 11) 0.10.20.4g/kg/ 1,25(OH)2D351020 g/kg/ 2 腿 腿 0.4g/kg 1,25(OH)2D3 5 0.00750.0150.03g/kg/ 12 12) ) 12,13) 1 12 腿 DXA pqctperipheral Quantitative Computed TomographyStiffnessPeak Load AUC 腿 3 0.03g/kg/ 腿 腿 腿 meanse (n=1215)sham OVX 0.0075μg/kg 0.015μg/kg 0.03μg/kg * P 0.05** P 0.01*** P 0.001 vs OVX Dunnett s test 14
腿 腿 OVX(ng/kg/day) OVX(ng/kg/day) meanse (n=910)* P 0.05** P 0.01*** P 0.001 vs OVX Dunnett s test 2 16 0.07g/kg/ 腿 3 12,13) 1 0.00750.0150.03g/kg/ 12 L3 2 0.01750.0350.07g/kg/ 16 腿 14) 0.0150.05g/kg/ 4 15
16 ED008JP 15) Ca (ALF) 12 Ca 1 uca untxbap Ca 1 uca 1.0g 20 ALF 1.0g 20 untx BAP ALF Ca ALF 10 0 untx 10 0 BAP ED-71 1.0 g μ ALF 1.0 g μ -10-10 % -20 p0.003 (Student s t-test) % -20-30 -30-40 -20 0 20 40 60 1uCa(mg/day) -40-20 0 20 40 60 1uCa(mg/day) 16
VII.-1(3) 1 16) 0.75g Cmax (pg/ml) 80.917.9 (n=10) kel AUC24h (pgh/ml) 1,368327 (n=9) AUClast Tmax(h) Cmax AUCinf t1/2(h) (pg/ml) (h -1 ) (pgh/ml) (pgh/ml) 3.41.2 99.812.7 53.011.4 0.013610.00264 3,947580 6,5611,245 MeanSD, n=31 0.75g 1 1 14 17) CL/F Tmax(h) t1/2(h) (L/h) 14 5.42.8 (n=10) 6.02.8 (n=10) 243.528.2 (n=10) 48.411.5 (n=9) 48.74.9 (n=10) 4,964597 (n=10) AUCinf (pgh/ml) 4,9551,489 (n=9) 17,8022,051 (n=10) 0.1640.048 (n=9) CLss/F(L/h) 0.1530.019 (n=10) CL/FCLss/F MeanSD 0.11.0g 1 1 15 13 CmaxCminAUC24h t1/2 0.11.0g 4) 17
2 6) 0.50.751.0g 1 1 48 pg/ml 12 24 48 * 0.5g 238.180.9 249.764.4 246.0136.3 244.596.8 (n=49) (n=48) (n=44) (N=141) 0.75g 339.7108.8 351.595.3 306.2150.1 333.4119.8 (n=54) (n=52) (n=47) (N=153) 1.0g 514.3674.5 469.9135.2 401.3140.2 465.0417.1 (n=53) (n=51) (n=45) (N=149) nn* 12 24 48 (MeanSD) 3 18) 10 Child-Pugh ClassA8 ClassB2 0.75g 18 Cmax pg/ml AUClast pgh/ml (Child-Pugh ClassA) 99.719.1 3,622731 73.9 2,936 (Child-Pugh ClassB) (63.1, 84.6) (2,622, 3,250) 16) 99.812.7 3,947580 Child-Pugh ClassAn=8n=31 (Mean±SD) Child-Pugh ClassBn=2Mean(Min,Max) 4 CLcr 2) 2) 4,15, 19) CLcr (pg/ml) n=n= CLcr(mL/min)* 1030 384.3145.7(N=17) 0.75g 3060 322.9114.8(N=331) 144 6070 304.889.4(N=19) 70 254.281.6(N=15) 0.75g 75 302.3101.0(N=232) 144 75 352.5129.1(N=150) 1.0g 15 316.196.3**(n=6) 1.0g 14 289.6114.1***(n=22) 1.0g 12 260.455.6****(N=80) (Mean±SD) * Cockcroft-Gault **1314151524 ***13141424 ****24812
110.75g 110.5g 1 16) 0.75g Cmax (pg/ml) AUClast (pgh/ml) 10 100.4211.02 4,094445 30 95.378.89 3,879577 (Mean±SD, n=15) 2 17) 0.75g 1 1 14 CYP3A4 90% 90% AUClast 0.964 0.6903 1.3468 0.848 0.6743 1.0654 0.874 0.7535 1.0136 0.929 0.7178 1.2029 Cmax 1.158 0.8766 1.5306 0.809 0.6669 0.9826 0.958 0.7526 1.2185 0.894 0.6302 1.2684 882 15% 20) 882 3674 1 1-19
ka1.62 h -1 20) 21) 0.05 1g/kg F 95.5 88.5 1g/kg F 75.3 VII.-1(3) CL/F0.101 L/h 20) Vc/F10.5 L 20) 1100ng/mL 94.296.2% in vitro 22) VII.-1(3) 75% VII.-4(5) 23) 15 3 H- 0.050.5 5g/kg 6 24) 0.05g/kg 3 H-7.3 49.3pg eq./ml 2 AUCinf AUCinf 6% 20
VII.-4(5) 25) 3 H- 0.05g/kg 1 6 24 3 H- 1 1 14 1 6 24 96 168 308 47 346 34 294 3 151 6 105 4 178 26 197 17 177 3 100 8 62 2 3 1 4 1 3 1 1 0 1 0 4 1 4 0 3 1 2 0 1 0 41 10 40 7 40 9 15 2 11 3 47 10 51 8 50 3 40 7 26 3 36 6 37 3 26 1 16 1 12 1 49 5 56 6 50 2 32 1 29 2 140 30 57 7 40 1 22 1 16 1 10 1 25 3 16 2 10 2 5 1 7 1 32 5 35 2 27 3 16 2 9 3 16 1 15 1 10 0 6 1 31 5 46 6 38 5 16 1 11 1 10 2 15 1 13 2 7 1 5 0 38 7 44 3 33 3 14 2 12 1 16 3 42 5 37 1 15 3 13 1 14 3 50 6 57 3 29 3 19 0 8 2 24 3 22 1 18 2 10 0 8 1 17 6 20 1 12 1 5 0 pg eq. of / g or ml 4 24 24(OH)ED-712 3-hydroxypropyloxy ED-138 2 3-hydroxypropyloxy 3-(1,25-(OH)2D3-2 -yloxy)propionic acid 3 26) 2 3-hydroxypropyloxy 24 27) in vitro 28) 21
H H 3C CH 3 CH 3 H H 3C OH H CH 2 HO OH H H O H HO ED-71 H H 3C CH 3 H H 3C OH CH3 H H 3C CH 3 H OH H 3C OH CH3 H H CH 2 CH 2 HO H HO H OH H HO OH H H O H 3-(1,25-(OH) 2 D 3-2βyloxy)propionic acid ED-138 HO 24(OH)ED-71 12 CYP CYP1A11A22A62B62C82C92C182C192D6 2E13A4 4A11 in vitro CYP NADPH NADHNADP+ NAD+ CYP CYP CYP 29) 0.75g 1 1 14 17) 3 H- 7 2.63% 55.89% 30) 22
VII.-6(1) VII.-6(1) 23
VIII.-6.(1)VIII.-10. IX.-2.(3)VII.-4.(3) (1) (2) (3) (1) VIII.-8.(2) CLcr 30mL/min 11.0mg/dL PTHrP PTH PTH D (2) (3)VIII.-8.(2) 24
(1) (2) 36 1 (3) (4) 倦 (1)VIII.-2.VIII.-10.IX.-2.(3) (2)(3)(4)VIII.-8.(2) D PTH 25 D D3 D PTH
D3 802 309 38.5% 456 163 20.3% 120 15.0% 15 1.9% 12 1.5% 1) 10.4mg/dL 11.0mg/dL 2) 11.0mg/dL 11.5% 倦 2 30.9% 2) 11.0mg/dL 1) D3 11.0mg/dL 802 12 1.5% 12 11.112.0mg/dL 12 526 5 1.0% 36 1 1 1 0.5g V.-2 VIII.-5.VIII.-6. 2) D3 3) 802 7 0.9% D3 528 6 1.1% 526 5 1.0% 26
2% 2% -GTP ASTGOTALTGPTLDH BUN 20.3% Al-P 15.0% 1) 10.4mg/dL 11.0mg/dL 802 3 2 802 309 456 38.5% 163 (20.3%) 132 (16.5%) 13 (1.6%) 9 (1.1%) 9 (1.1%) 7 (0.9%) 5 (0.6%) 5 (0.6%) 6 (0.7%) 4 (0.5%) 3 (0.4%) 3 (0.4%) 3 (0.4%) 3 (0.4%) 2 (0.2%) 2 (0.2%) 2 (0.2%) 1 (0.1%) 1 (0.1%) 1 (0.1%) 1 (0.1%) 1 (0.1%) 1 (0.1%) 1 (0.1%) 1 (0.1%) 27
5 (0.6%) 5 (0.6%) 3 (0.4%) 2 (0.2%) 2 (0.2%) 2 (0.2%) 1 (0.1%) 1 (0.1%) 1 (0.1%) 1 (0.1%) 1 (0.1%) 扁 1 (0.1%) 1 (0.1%) 5 (0.6%) 3 (0.4%) 2 (0.2%) 1 (0.1%) 4 (0.5%) 2 (0.2%) 1 (0.1%) 1 (0.1%) 4 (0.5%) 3 (0.4%) 1 (0.1%) 2 (0.2%) 2 (0.2%) 1 (0.1%) 1 (0.1%) 4 (0.5%) 1 (0.1%) 2 (0.2%) 1 (0.1%) 1 (0.1%) 1 (0.1%) 2 (0.2%) 1 (0.1%) 1 (0.1%) 1 (0.1%) 1 (0.1%) 1 (0.1%) 1 (0.1%) MedDRA/J version 8.0. 28
(1) 0.125 g/kg/ 6.8 0.5g/kg/27.0 0.3g/kg/ (2) (3) VIII.-2.IX.-2.(3)VII.-4.(3) 1 1 0.5g 1 1 0.5g 1 1 0.75g (1) PTP PTP PTP 穿 (2) 29
SD 2 C 0.72.8 7.0 Crl:CDSD 1 1 24 C IX.-2.(4) 2) 30
g/kg ddy 00.040.21 疼 SD 00.040.21 00.040.21 herg herg 0.13.13 IC20 in vitro K CHO mol/l 2.84mol/L 00.040.21 / ph SD 00.040.21 BaSO4 ddy 00.040.21 acetylcholine, histamine,bacl2 in vitro 110-9 110-8 g/ml 6 SD 1 5 148.1167.3g 120.0136.1g 034.5 6.71015g/kg 21 1015g/kg 418 6.7g/kg 10g/kg 15g/kg 腿 7 1 1 9.8kg 7.88.7kg 0.81.63.2g/kg 14 1.63.2g/kg 0.81.6g/kg 34 0.8g/kgCa 31
6 SD 1 00.020.10.5g/kg/6 00.0005 0.0050.05g/kg/ 59 1 00.0030.010.030.1g/kg/6 00.00030.0030.03g/kg/9 00.0050.030.06/0.045*g/kg/ Ca Ca D3VD3 1 2 1 0.02g/kg/ 1 0.005g/kg/ 6 0.01g/kg/ 1 0.003g/kg/ 6 0.005g/kg/ 9 * 11 0.06g/kg/ 0.045g/kg/ 67 SD 1 25 220253g 89 SD 1 25 179212g 00.0040.020.1g/kg/ 63 9 14 2 7 0.02g/kg/0.1g/kg/ SD 10 187250g 1 22 1 12 娩 00.0320.1250.5g/kg/ 717 0.032g/kg/0.125g/kg/0.5g/kg/ 餌 F1 1 0.125g/kg/ 0.5g/kg/ 娩 F1 0.5g/kg/ 0.125g/kg/ 0.125g/kg/F1 SD 1517 273373g 1 16 1 5 00.050.160.51.65g/kg 0.16g/kg 15 5 Japanese White 1 15 2.83.9kg 00.012 0.060.3g/kg/ 618 28 32
0.06g/kg/ 餌 0.3 g/kg/ 0.06g/kg/0.3g/kg/ 1 20 SD 1112 00.0080.0320.125g/kg/ 7 20 Ca 0.125g/kg/0.032 g/kg/f1 0.125g/kg/ 35) 3 in vitro Ames CHL ICR 50g/kg 24 36) 6 B6C3F1:Crlj 1 55 21.027.1g 17.622.2g 00.030.060.1g/kg/ 7 2 104 24 37) 6 Crl:CDSD1 60 186241g 142192g 00.0050.020.05/0.03*g/kg/ 7 2 104 C 0.02g/kg/ 0.02g/kg/ 0.02g/kg/ 0.02g/kg/ 0.05/0.03g/kg/ 0.02g/kg/ C 0.05/0.03g/kg/ 1 * 58 0.05g/kg/ 0.03g/kg/ 38) ASA PCA PCA 33
0.5g0.75g 3 VIII14 0.5g100 PTP140 PTP 0.75g100 PTP140 PTP500 PTP 700 PTP PTP PTP 2011 1 21 34
2011 1 21 0.5g 22300AMX00416 0.75g22300AMX00417 2011 3 11 2011 1 21 2019 1 20 8 HOT(9 ) 0.5g 120425402 3112006M1022 622042502 0.75g 120426102 3112006M2029 622042602 35
1) NIH Consensus Statement 2000, March 27-29, 17(1), 1-45 2) 3) 4) 15 5) 6) 7) 8) in vitro 9) 10) 11) 12) OVX 13) OVX 14) 15) 12 16) 17) 18) 19) 14 20) 21) 22) in vitro 23) 24) 25) 26) 27) 28) in vitro 29) in vitro 30) 31) 32) 33) 34) 35) 36) 37) 38) 36
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