1) Bell A. Morphologic evaluation of erythrocytes. In, Clinical hematology: Principles, procedures, correlations, 2nd ed. Stiene-Martin EA, Lotspeich-Steininger CA, Koepke JA eds. Lippincott-Raven, Philadelphia, Pennsylvania. 1998; 87-105.
2) Clinical Pathology Reference Intervals - Sprague-Dawley Rat, Bristol-Myers Squibb, Drug Safety Evaluation, DSE Archive, New Brunswick, New Jersey, Nov 2005.
3) Clinical Pathology Reference Intervals - Dog, Bristol-Myers Squibb, Drug Safety Evaluation, DSE Archive, New Brunswick, New Jersey, Nov 2006.
4) Clinical Pathology Reference Intervals - Cynomolgus Monkey, Bristol-Myers Squibb, Drug Safety Evaluation, DSE Archive, New Brunswick, New Jersey, Sep 2007.
5) Morton D, Alden CL, Roth AJ, et al. The Tg rasH2 mouse in cancer hazard identification. Toxicol Pathol 2002; 30: 139-146.
6) Kanno H, Tanakamaru Z, Ishimura Y, et al. Historical background data in CB6F1-Tg-rasH2 mice and CB6F1-nonTg-rasH2 mice over a 26 week experimental period. J Toxicol Pathol 2003; 16:
267-274.
7) Nambiar PR, Turnquist SE, Morton D. Spontaneous tumor incidence in rasH2 mice:Review of internal data and published literature. Toxicol Pathol 2012; 40: 614-623.
8) Usui T, Mutai M, Hisada S, et. al. CB6F1-rasH2 mouse: overview of available data. Toxicol Pathol 2001; 29(Suppl.): 90-108.
9) Mutai M, Sano F, Kusakabe M, et al. Detection of carcinogenic potential of diethylstilbestrol and N-Methyl-N-Nitrosourea by the alternative testing model using Tg-rasH2 mouse. In, Appendix I:
ILSI Alternatives Methods for Carcinogenicity Testing Workshop Poster Abstracts. Toxicol Pathol 2001; 29(Suppl.): 198-322 (240-241).
CTD 第 2 部
2.6 非臨床試験の概要文及び概要表
2.6.7 毒性試験概要表
ブリストル・マイヤーズ株式会社
目次
1 毒性試験：一覧表 ... 3 2 トキシコキネティクス：トキシコキネティクス試験の一覧表 ... 6 3 トキシコキネティクス試験：試験成績の一覧表 ... 8 4 毒性試験：被験物質（バッチ毎）一覧 ... 14 5 単回投与毒性試験 ... 16 6 反復投与毒性試験：重要な試験以外の試験 ... 18 7 反復投与毒性試験：重要な試験 ... 19 8 In vitro遺伝毒性試験 ... 47 9 In vivo遺伝毒性試験 ... 50 10 がん原性試験 ... 51 11 生殖発生毒性試験：重要な試験以外の試験 ... 63 12 生殖発生毒性試験：受胎能及び着床までの初期胚発生まで関する試験 ... 64 13 生殖発生毒性試験：胚・胎児発生に関する試験 ... 67 14 生殖発生毒性試験：出生前及び出生後の発生並びに母体の機能に関する試験 ... 73 15 新生児を用いた試験 ... 79 16 局所刺激性試験 ... 79 17 その他の毒性試験 ... 80
Abbreviations: ; BMS = Bristol-Myers Squibb, BMS = Bristol-Myers Squibb, BMS = Bristol-Myers Squibb, CHO = Chinese hamster ovary;
GD = Gestation day; LD = Lactation day; LE = Long Evans; NA = Not applicable; NZW = New Zealand White; SD = Sprague Dawley All footnotes are available as table end notes.
1 毒性試験：一覧表
Table 2.6.7.1: Toxicology: Overview
Study Type Species/Strain Method of
Administration Duration of
Dosing Doses (mg/kg)a GLP
Compliance Testing Facility
Study No./
Document Control No.
Location in Dossier Single-Dose
Toxicity Mouse/Crl:CD-1 Oral (gavage) 1 day 0, 200, 600, 2000 GLP BMS DM07027/
930024006 4.2.3.1.1 Rat/Crl:CD (SD) Oral (gavage) 1 day 0, 200, 600, 2000 GLP BMS DM07028/
930023864 4.2.3.1.2 Dog/beagle Oral (gavage) 1 day 0, 30, 100, 300 nonGLP BMS DN06076/
930023760 4.2.3.1.3 Repeat-Dose
Toxicity Mouse/CByB6F1
Tg(HRAS)2Jic Oral (gavage) 28 days 0, 50, 150, 500 GLP DM09022/
930050534 4.2.3.4.2.1
Rat/Crl:CD (SD) Oral (gavage) 2 weeks 0, 30, 100, 300 nonGLP BMS DN07002/
930023931 4.2.3.2.1
Rat/Crl:CD (SD) Oral (gavage) 1 month 0, 30, 100, 600 GLP BMS DM07024/
930024094 4.2.3.2.2 Rat/Crl:CD (SD) Oral (gavage) 1 month BMS-650032:
0, 30, 60 BMS-790052:
0, 10,
GLP
60
BMS DS08126/
930035562 4.2.3.2.3
Rat/Crl:CD (SD) Oral (gavage) 6 months 0. 40, 80, 200 GLP DM08025/
930039270 4.2.3.2.4
Dog/beagle Oral (capsule) 1 month 0, 20, 60, 300 GLP BMS DM07020/
930024088 4.2.3.2.5
Dog/beagle Oral (capsule) 9 months 0, 15, 50, 100 GLP DM08026/
930038894 4.2.3.2.6 Monkey/
cynomolgus Oral (gavage) 1 week 0, 30, 150, 300 nonGLP BMS DM08018/
930032152 4.2.3.2.7
Abbreviations: ; BMS = Bristol-Myers Squibb, BMS = Bristol-Myers Squibb, BMS = Bristol-Myers Squibb, CHO = Chinese hamster ovary;
GD = Gestation day; LD = Lactation day; LE = Long Evans; NA = Not applicable; NZW = New Zealand White; SD = Sprague Dawley All footnotes are available as table end notes.
Table 2.6.7.1: Toxicology: Overview (Continued)
Study Type Species/Strain Method of
Administration Duration of
Dosing Doses (mg/kg)a GLP
Compliance Testing Facility
Study No./
Document Control No.
Location in Dossier Repeat-Dose
Toxicity (Continued)
Monkey/
cynomolgus Oral (gavage) 1 month BMS-650032 0, 72, :
129.5 BMS-790052 0, 15, :
GLP
50
BMS DS08143/
930035546 4.2.3.2.8
Monkey/
cynomolgus Oral (gavage) 3 months BMS-650032 0, 45, : BMS-79005280 0, 15, :
GLP
50
BMS DM09008/
930039780 4.2.3.2.9
Genotoxicity Bacterial Reverse Mutation
S. typhimurium (TA98, TA100, TA1535, TA1537) and E. coli (WP2 uvrA)
In vitro NA Initial:
1.5-5000 μg/plate Confirmatory:
150-5000 μg/plate
GLP DS07123/
930024111 4.2.3.3.1.1
Cytogenetics CHO cells In vitro 3 h ± S9
20 h −S9 +S9: 2.5 - 40 μg/mL
−S9: 2.5 - 60 μg/mL GLP BMS DS07112/
930024092 4.2.3.3.1.2 In vivo
micronucleus Rat/Crl:CD (SD) Oral (gavage) 3 days 0, 250, 500, 1000,
2000 GLP BMS DS08016/
930029814 4.2.3.3.2.1 Carcinogeni-
city Mouse/
CByB6F1-Tg (HRAS)2Jic hemizygous
Oral (gavage) 26 weeks 0 (water), 0 (vehicle),
25, 100, 200 GLP DM11012/
930069464 4.2.3.4.2.2
Rat/
Crl:CD (SD) Oral (gavage) 2 years M: 0 (water), 0 (vehicle), 50, 75, 125
F: 0 (water), 0 (vehicle), 40, 60, 80,
GLP DM11023/
930070680 4.2.3.4.1.1
Abbreviations: ; BMS = Bristol-Myers Squibb, BMS = Bristol-Myers Squibb, BMS = Bristol-Myers Squibb, CHO = Chinese hamster ovary;
GD = Gestation day; LD = Lactation day; LE = Long Evans; NA = Not applicable; NZW = New Zealand White; SD = Sprague Dawley All footnotes are available as table end notes.
Table 2.6.7.1: Toxicology: Overview (Continued)
Study Type Species/Strain Method of
Administration Duration of
Dosing Doses (mg/kg)a GLP
Compliance Testing Facility
Study No./
Document Control No.
Location in Dossier Reproductive and Developmental Toxicity
Fertility and early embryonic development
Rat/Crl:CD (SD) Oral (gavage) M: 4 weeks premating until necropsy F: 2 weeks premating until GD 7
0, 50, 200, 600 GLP DN08069/
930058197 4.2.3.5.1.1
Embryo-fetal
development Mouse/Crl:CD-1 Oral (gavage) 10 days 0, 60, 125, 250, 500 nonGLP BMS DN08014/
930068598 4.2.3.5.2.1
Mouse/Crl:CD-1 Oral (gavage) GD 6-15 0, 10, 50, 250, 500 GLP DN08022/
930044126 4.2.3.5.2.3 Rabbit/Hra:
(NZW) SPF Oral (gavage) 13 days 0, 50, 100, 200, 400 nonGLP BMS DN08021/
930068624 4.2.3.5.2.2 Rabbit/Hra:
(NZW) SPF Oral (gavage) GD 7-19 0, 50, 100, 200 GLP BMS DN08056/
930043164 4.2.3.5.2.4 Pre- and post-
natal
development
Rat/Crl:CD (SD) Oral (gavage) GD 6 - LD 20 0, 40, 125, 400 GLP DN11186/
930069737 4.2.3.5.3.1 Other Toxicity Studies
Phototoxicity Balb/c 3T3 mouse
fibroblasts In vitro 2.5 h 0.11, 0.2, 0.36, 0.65, 3.6, 6.5, 11.0, 20.0, 36.0, 65.0 mg/L
GLP DM07031/
930024089 4.2.3.7.7.1
Rats/Crl:LE Oral (gavage) 1 day 0, 60, 325, 600 GLP DM08016/
930037752 4.2.3.7.7.2 a Unless otherwise specified. For Repeat-Dose Toxicity, the highest NOAEL (no-observed-adverse-effect level) is underlined.
Abbreviations: Tg-rasH2 (nontransgenic) = CByB6F1 hybrid; Tg-rasH2 (transgenic) = CByB6F1-Tg(HRAS)2Jic hemizygous 2 トキシコキネティクス：トキシコキネティクス試験の一覧表
Table 2.6.7.2: Toxicokinetics: Overview of Toxicokinetics Studies
Type of Study Test System Method of
Administration Doses
(mg/kg) GLP
Compliance Study No./
Document Control No. Location in Dossier Ten-day range finding Mouse Oral (gavage) 0, 60, 125, 250, 500 nonGLP DN08014/930068598 4.2.3.5.2.1 Embryo-fetal development Mouse Oral (gavage) 0, 10, 50, 250, 500 GLP DN08022/930044126 4.2.3.5.2.3 One-month exploratory
toxicity Mouse/Tg-rasH2
(nontransgenic) Oral (gavage) 0, 50, 150, 500 GLP DM09022/930050534 4.2.3.4.2.1 Twenty-six week
carcinogenicity Mouse/Tg-rasH2
(transgenic) Oral (gavage) 0 (water), 0 (vehicle),
25, 100, 200 GLP DM11012/930069464 4.2.3.4.2.2
Single-dose phototoxicity Rat Oral (gavage) 0, 60, 325, 600 GLP DM08016/930037752 4.2.3.7.7.2
Three-day micronucleus Rat Oral (gavage) 0, 250, 500, 1000, 2000 GLP DS08016/930029814 4.2.3.3.2.1 Two-week exploratory
toxicity Rat Oral (gavage) 0, 30, 100, 300 nonGLP DN07002/930023931 4.2.3.2.1
One-month toxicity Rat Oral (gavage) 0, 30, 100, 600 GLP DM07024/930024094 4.2.3.2.2
One-month combination
toxicity Rat Oral (gavage) BMS-650032:
0, 30, 60 BMS-790052
GLP 0, 10, 60 :
DS08126/930035562 4.2.3.2.3
Fertility and early
embryonic development Rat Oral (gavage) 0, 50, 200, 600 GLP DN08069/930058197 4.2.3.5.1.1
Pre- and postnatal
development Rat Oral (gavage) 0, 40, 125, 400 GLP DN11186/930069737 4.2.3.5.3.1
Six-month toxicity Rat Oral (gavage) 0, 40, 80, 200 GLP DM08025/930039270 4.2.3.2.4
Two-year carcinogenicity Rat Oral (gavage) M: 0 (water), 0 (vehicle), 50, 75, 125
F: 0 (water), 0 (vehicle), 40, 60, 80
GLP DM11023/930070680 4.2.3.4.1.1
Thirteen-day range finding Rabbit Oral (gavage) 0, 50, 100, 200, 400 nonGLP DN08021/930068624 4.2.3.5.2.2 Embryo-fetal development Rabbit Oral (gavage) 0, 50, 100, 200 GLP DN08056/930043164 4.2.3.5.2.4 Single-dose toxicokinetic
and tolerability Dog Oral (capsule) 0, 30, 100, 300 nonGLP DN06076/930023760 4.2.3.1.3
One-month toxicity Dog Oral (capsule) 0, 20, 60, 300 GLP DM07020/930024088 4.2.3.2.5
Nine-month toxicity Dog Oral (capsule) 0, 15, 50, 100 GLP DM08026/930038894 4.2.3.2.6
Abbreviations: Tg-rasH2 (nontransgenic) = CByB6F1 hybrid; Tg-rasH2 (transgenic) = CByB6F1-Tg(HRAS)2Jic hemizygous
Table 2.6.7.2: Toxicokinetics: Overview of Toxicokinetics Studies (Continued)
Type of Study Test System Method of
Administration Doses
(mg/kg) GLP
Compliance Study No./
Document Control No. Location in Dossier One-week exploratory
toxicity Monkey Oral (gavage) 0, 30, 150, 300 nonGLP DM08018/930032152 4.2.3.2.7
One-month combination
toxicity Monkey Oral (gavage) BMS-650032:
0, 72, 129.5 BMS-790052
GLP 0, 15, 50 :
DS08143/930035546 4.2.3.2.8
Three-month combination
toxicity Monkey Oral (gavage) BMS-650032:
0, 45, 80 BMS-790052
GLP 0, 15, 50 :
DM09008/930039780 4.2.3.2.9
All footnotes are available as table end notes.
3 トキシコキネティクス試験：試験成績の一覧表
Table 2.6.7.3A: Toxicokinetics: Overview of Toxicokinetics Data
Daily Dose (mg/kg)
Study Duration
Steady-State BMS-650032a Cmax (μg/mL)
Mice Rats Dogs Monkeys Female
Rabbits Humans b
M F M F M F M F
3.3 12 weeks 0.419
10 3 weeks 0.250
15 9 months 2.38 6.29
20 1 month 1.69 6.12
25 6 months 2.06 3.29
30 2 weeks 1.01 1.19
1 month 0.290 0.306
1 month 0.182 0.433
1 day 9.83 5.96
1 week 0.168 0.070
40 2 months 6.66
6 months 1.16 2.65
2 years 7.47
45 3 months 0.919 1.11
50 1 month 4.02 7.43
3 weeks 6.39
2 weeks 5.66
8 weeks 13.7
2 years 3.82
9 months 14.9 26.8
13 days 0.062
3 weeks 0.128
60 10 days 18.9
3 days 2.39
1 month 6.65 10.8
2 years 27.6
1 month 28.9 26.3
72 1 month 1.13 2.37
75 2 years 8.36
80 6 months 8.67 22.7
2 years 39.6
All footnotes are available as table end notes.
Table 2.6.7.3A: Toxicokinetics: Overview of Toxicokinetics Data (Continued)
Daily Dose (mg/kg)
Study Duration
Steady-State BMS-650032a Cmax (μg/mL)
Mice Rats Dogs Monkeys Female
Rabbits Humans b
M F M F M F M F
80 3 months 6.42 2.94
100 6 months 54.4 68.7
2 weeks 9.73 12.3
1 month 11.1 13.7
13 days 0.122
3 weeks 0.341
1 day 85.4 85.9
9 months 40.8 59.7
125 10 days 91.8
2 months 32.1
2 years 29.7
129.5 1 month 9.64 10.0
150 1 month 48.3 72.1
1 week 0.555 0.749
200 6 months 153 219
2 weeks 50.1
8 weeks 45.6
6 months 38.7 124
13 days 0.549
3 weeks 0.511
250 10 days 203
3 weeks 69.6
3 days 39.3
300 2 weeks 19.6 22.6
1 day 49.8 97.8
1 month 114 c 106 c,d
(121, 91.3, 50.9)
1 week 188 47.0
325 3 days 63.2
400 2 months 39.6
13 days 0.861
All footnotes are available as table end notes.
Table 2.6.7.3A: Toxicokinetics: Overview of Toxicokinetics Data (Continued)
Daily Dose (mg/kg)
Study Duration
Steady-State BMS-650032a Cmax (μg/mL)
Mice Rats Dogs Monkeys Female
Rabbits Humans b
M F M F M F M F
500 10 days 180
3 weeks 117
1 month 118 163
3 days 61.0
600 3 days 115
2 weeks 30.3
1 month 24.7 43.4
8 weeks 30.0
1000 3 days 60.4
2000 3 days 67.1
Source Data: Document Control Nos.:
Mouse: 930068598, 930044126, 930050534, 930069464
Rat: 930037752, 930029814, 930023931, 930024094, 930035562, 930058197, 930069737, 930039270, 930070680 Rabbit: 930068624, 930043164
Dog: 930023760, 930024088, 930038894 Monkey: 930032152, 930035546, 930039780 Human: 930050489
a For Cmax values for other test articles evaluated in selected combination toxicity studies with BMS-650032, refer to source data.
b Week 12 human Cmax value in HCV-infected subjects given 200 mg tablet twice per day (BID; AI447016). The softgel capsule given 100 mg BID (200 mg/day), which is the anticipated commercial form, provides a similar exposure as a 200 mg BID tablet.
c Vomitus was observed within 2 h post dose in 2 females on Day 1, and 1 male and 1 female on Day 28. These animals were included in the mean calculations.
d Value represents the mean of 2 dogs (1 dog was excluded from the mean calculations due to emesis with partially dissolved dosing capsule present at 1 h post dose on Days 1 and 28); no standard deviation could be calculated. Individual values are shown in parentheses.
All footnotes are available as table end notes.
Table 2.6.7.3B: Toxicokinetics: Overview of Toxicokinetics Data
Daily Dose (mg/kg)
Study Duration
Steady-State BMS-650032a AUC (μg•h/mL)
Mice Rats Dogs Monkeys Female
Rabbits Humans b
M F M F M F M F
3.3 12 weeks 1.26 1.75 3.69
10 3 weeks 0.851
15 9 months 5.46 15.6
20 1 month 4.58 16.3
25 6 months 13.5 13.8
30 2 weeks 4.09 4.20
1 month 1.88 1.34
1 month 2.19 2.11
1 day 23.0 15.5
1 week 0.483 0.240
40 2 months 26.8
6 months 3.99 11.6
2 years 51.5
45 3 months 2.80 2.87
50 1 month 16.1 29.0
3 weeks 19.1
2 weeks 29.9
8 weeks 53.0
2 years 20.7
9 months 47.2 80.9
13 days 0.760
3 weeks 1.17
60 10 days 57.8
3 days 12.9
1 month 27.9 54.9
2 years 162
1 month 102 98.5
72 1 month 4.57 7.77
75 2 years 58.1
80 6 months 39.3 144
2 years 202
3 months 31.7 13.9
All footnotes are available as table end notes.
Table 2.6.7.3B: Toxicokinetics: Overview of Toxicokinetics Data (Continued)
Daily Dose (mg/kg)
Study Duration
Steady-State BMS-650032a AUC (μg•h/mL)
Mice Rats Dogs Monkeys Female
Rabbits Humans b
M F M F M F M F
100 6 months 256 417
2 weeks 135 155
1 month 83.2 98.2
13 days 2.11
3 weeks 2.79
1 day 578 486
9 months 223 380
125 10 days 603
2 months 282
2 years 193
129.5 1 month 73.9 60.2
150 1 month 171 426
1 week 5.44 6.16
200 6 months 983 1,600
2 weeks 545
8 weeks 454
6 months 321 684
13 days 5.02
3 weeks 4.40
250 10 days 1,810
3 weeks 737
3 days 533
300 2 weeks 147 294
1 day 312 923
1 month 1,410 c 1,360 c,d
(1,730;
982; 412)
1 week 982 411
325 3 days 596
400 2 months 711
13 days 10.6
500 10 days 2,380
3 weeks 1,740
All footnotes are available as table end notes.
Table 2.6.7.3B: Toxicokinetics: Overview of Toxicokinetics Data (Continued)
Daily Dose (mg/kg)
Study Duration
Steady-State BMS-650032a AUC (μg•h/mL)
Mice Rats Dogs Monkeys Female
Rabbits Humans b
M F M F M F M F
500 1 month 922 2,310
3 days 960
600 3 days 1,440
2 weeks 373
1 month 227 371
8 weeks 386
1000 3 days 1,190
2000 3 days 1,090
Source Data: Document Control Nos.
Mouse: 930068598, 930044126, 930050534, 930069464
Rat: 930037752, 930029814, 930023931, 930024094, 930035562, 930058197, 930069737, 930039270, 930070680 Rabbit: 930068624, 930043164
Dog: 930023760, 930024088, 930038894 Monkey: 930032152, 930035546, 930039780 Human: 930050489
a For AUC values for other test articles evaluated in selected combination toxicity studies with BMS-650032, refer to source data.
b Week 12 human Cmax value in HCV-infected subjects given 200 mg tablet twice per day (BID; AI447016). The softgel capsule given 100 mg BID (200 mg/day), which is the anticipated commercial form, provides a similar exposure as a 200 mg BID tablet.
c Vomitus was observed within 2 h post dose in 2 females on Day 1, and 1 male and 1 female on Day 28. These animals were included in the mean calculations.
d Value represents the mean of 2 dogs (1 dog was excluded from the mean calculations due to emesis with partially dissolved dosing capsule present at 1 h post dose on Days 1 and 28); no standard deviation could be calculated. Individual values are shown in parentheses.
All footnotes are available as table end notes.
4 毒性試験：被験物質（バッチ毎）一覧
Table 2.6.7.4: Toxicology: Drug Substance
Batch No. Purity %
(Assay “As is”)a Formulation Type of Study Study No./
Document Control No.
BMS-650032- Single-dose oral toxicokinetic and tolerability study in dogs DN06076/
930023760
22 Two-week oral exploratory toxicity study in rats DN07002/
930023931
0025 Neutral red uptake phototoxicity assay in Balb/c 3T3 mouse
fibroblasts DM07031/
930024089 Ames reverse-mutation study in salmonella typhimurium and
Escherichia coli DS07123/
930024111 Cytogenetics study in Chinese hamster ovary cells DS07112/
930024092
Single-dose oral toxicity study in mice DM07027/
930024006 Ten-day oral range finding study in pregnant mice DN08014/
930068598
Single-dose oral toxicity study in rats DM07028/
930023864 Three-day oral micronucleus study in male rats DS08016/
930029814
One-month oral toxicity study in rats DM07024/
930024094
One-month oral toxicity study in dogs DM07020/
930024088
7929 Single-dose oral phototoxicity study of the eyes and skin of male
Long-Evans pigmented rats DM08016/
930037752 One-week oral exploratory toxicity study in monkeys DM08018/
930032152 Oral study of fertility and early embryonic development in rats DN08069/
930058197 Oral study of embryo-fetal development in mice DN08022/
930044126 Thirteen-day oral range finding study in pregnant rabbits DN08021/
930068624
*原薬1
*原薬1
*原薬2
*原薬2
＊新薬承認情報提供時に置き換え
All footnotes are available as table end notes.
Table 2.6.7.4: Toxicology: Drug Substance (Continued)
Batch No. Purity %
(Assay “As is”)a Formulation Type of Study Study No./
Document Control No.
7929 Oral study of embryo-fetal development in rabbits DN08056/
930043164 One-month oral combination toxicity study in rats DS08126/
930035562 One-month oral combination toxicity study in monkeys DS08143/
930035546
b Twenty-six week oral carcinogenicity study in
CByB6F1-Tg(Hras)2Jic hemizygous mice DM11012/
930069464
b One-month oral exploratory toxicity study in CByB6F1 hybrid mice DM09022/
930050534 Three-month oral combination toxicity study in monkeys DM09008/
930039780
b Two-year oral carcinogenicity study in rats DM11023/
930070680
7930 Six-month oral toxicity study in rats DM08025/
930039270
Nine-month oral toxicity study in dogs DM08026/
930038894
4321 Oral study of pre- and postnatal development in rats DN11186/
930069737
8128 Two-year oral carcinogenicity study in rats DM11023/
930070680
b Two-year oral carcinogenicity study in rats DM11023/
930070680 a Assay (“As is”) purity determined against a reference standard and corrected for total volatiles, water, and counterions. Assay (“As is”) purity is indicated in parenthesis.
b Additional values reflect reassay of batch to support extension of use date for use in toxicology studies.
*原薬2
*原薬2
*原薬2
*原薬2
＊新薬承認情報提供時に置き換え
Abbreviations: PEG = Polyethylene glycol; SD = Sprague Dawley; TPGS = d-α-tocopheryl polyethylene glycol 1000 succinate 5 単回投与毒性試験
Table 2.6.7.5: Single-Dose Toxicity
Species/Strain (GLP
Compliance)
Method of Administration (Vehicle/
Formulation)
Doses (mg/kg)
No. per Group and Gender
Observed Maximum Nonlethal Dose (mg/kg)
Approximate Lethal Dose
(mg/kg) Noteworthy Findings Study No./
Document Control No.
Mouse/
CD-1 (GLP)
Oral (gavage) (60% PEG-400 and 40% TPGS)
0, 200,
600, 2000 5 M, 5 F 600 2000 ≥ 200 mg/kg: Unformed, mucoid,
and/or liquid feces on Day 1;
perigenital soiling (fur) on Days 1-3.
200 and 600 mg/kg: Decreased (5-6%) mean body weight (M, Days 8 and 15).
2000 mg/kg
DM07027/
930024006
: Death or moribund euthanasia (4 M, 5 F) within 24 h of dosing with decreased activity, partially closed eyelids, ataxia, low/splayed body posture, recumbancy, decreased respiration, coolness to touch, cyanosis, and/or dehydration prior to death;
partial eyelid closure, decreased activity, dark discharge from eye, and transient body weight loss (11%, Day 3) in surviving M; macroscopic distension of stomach (with white/tan fluid and gas) and small and large intestines (with turbid fluid) and discoloration of gastric mucosa in F;
microscopic compression of gastric mucosa (minimal-mild), swelling/
vacuolation of epithelial cells on mucosal surface of glandular stomach and enterocytes at the villous tips in the small intestine (slight-mild), enterocyte extrusion (minimal-slight), necrosis of enterocytes within the cecum and of lymphocytes within the mantle zone of the ileal Peyer’s patches in 1 M.
Abbreviations: PEG = Polyethylene glycol; SD = Sprague Dawley; TPGS = d-α-tocopheryl polyethylene glycol 1000 succinate
Table 2.6.7.5: Single-Dose Toxicity (Continued)
Species/Strain (GLP
Compliance)
Method of Administration (Vehicle/
Formulation)
Doses (mg/kg)
No. per Group and Gender
Observed Maximum Nonlethal Dose (mg/kg)
Approximate Lethal Dose
(mg/kg) Noteworthy Findings Study No./
Document Control No.
Rat/
Crl:CD (SD) (GLP)
Oral (gavage) (60% PEG-400 and 40% TPGS)
0, 200,
600, 2000 5 M, 5 F 2000 > 2000 Clinically well tolerated at ≤ 600 mg/kg.
2000 mg/kg
DM07028/
: Body soiling, low incidences of decreased activity, partially closed eyelids, and low body posture in M on Day 1 and low incidences of scant feces in M and F;
decreased (6.7-8.5%) mean body weight in M on Days 3-15 and body weight loss (4.3%) in 1 F on Day 3.
930023864
Dog/
beagle (nonGLP)
Oral (capsule) (60% PEG-400 and 40% TPGS)
0, 30, 100,
300, 1 M, 1 F 300 > 300 Clinically well tolerated at ≤ 100 mg/kg.
300 mg/kg
DN06076/
930023760 : Emesis noted 10-60 mins
post dose in M and F.
Abbreviations: NOAEL = No-observed-adverse-effect level; PEG = Polyethylene glycol; SD = Sprague Dawley; TPGS = d-α-tocopheryl polyethylene glycol 1000 succinate 6 反復投与毒性試験：重要な試験以外の試験
Table 2.6.7.6: Repeat-Dose Toxicity: Nonpivotal Studies
Species/Strain (GLP
Compliance)
Method of Administration (Vehicle/
Formulation)
Duration
of Dosing Doses (mg/kg)
No. per Group and Gender
NOAEL
(mg/kg) Noteworthy Findings Study No./
Document Control No.
Rat/
Crl:CD (SD) (nonGLP)
Oral (gavage) 80% PEG-400/ 20%
TPGS
2 weeks 0, 30, 100,
300 6 M, 6 F 300 30, 100 mg/kg: No noteworthy findings 300 mg/kg
AUC(0-24h) values at 30, 100, and 300 mg/kg were up to 4.20, 155, and 294 μg•h/mL
: Slightly increased urine pH (+0.7 pH units), minor increased serum bilirubin in F (1.9× control), decreased kidney (15%) and heart weights (12%) in M.
Tissue Toxicokinetics: At necropsy (approximately 24 h after last dose), BMS-650032 was detected in liver (35.7-229 μg/g), heart (0.069-1.99 μg/g), and spleen (0.064-1.90 μg/g) at each dose level.
DN07002/
930023931
Monkey/
cynomolgus (nonGLP)
Oral (gavage) 60% PEG-400/ 40%
TPGS
1 week 0, 30, 150,
300 2 M, 2 F 300 ≥ 150 mg/kg: Decreased total cholesterol (0.64-0.82× predose) in 1 M at 150 mg/kg and in 1 F and 2 M at 300 mg/kg,
increased total bilirubin (4.0-1.93×) and decreased albumin (0.84-0.91×) in M at 300 mg/kg.
300 mg/kg
DM08018/
930032152
: Minimal bone marrow hypercellularity (due to an increase in the myeloid component, likely reflecting stimulation of leukocyte cell lines) in the sternum and rib in M.
Abbreviations: -- = No noteworthy findings; ♦ = Not conducted; NA = Not applicable; ND = Not defined; PEG = Polyethylene glycol; TK = Toxicokinetics; TPGS = d-α-tocopheryl polyethylene glycol 1000 succinate
* P ≤ 0.05, ** P ≤ 0.01 Dunnett’s Test All footnotes are available as table end notes.
7 反復投与毒性試験：重要な試験
Table 2.6.7.7A: Repeat-Dose Toxicity
Report Title: 28-Day Oral Exploratory Toxicity Study in CByB6F1 Hybrid Mice Study No.: DM09022 Species/Strain: Mouse/
CByB6F1 hybrid Duration of Dosing: 1 month Document Control No.: 930050534
Initial Age: ~ 10 weeks Duration of Post Dose: NA Location in Dossier: 4.2.3.4.2.1
Date of First Dose: 20 Method of Administration: Oral (gavage) Vehicle/Formulation: 60% PEG-400 and
40% TPGS GLP Compliance: GLP
Special Features: None
No-Observed-Adverse-Effect Level: ND
Daily Dose (mg/kg): (0) Control 50 150 500
Number of Animals:a M: 10 F: 10 M: 10 F: 10 M: 10 F: 10 M: 10 F: 10
Toxicokinetics: a
Cmax (μg/mL) ♦ ♦ 4.02 7.43 48.3 72.1 118 163
AUC(0-24h) (μg•h/mL) ♦ ♦ 16.1 29.0 171 426 922 2,310
Noteworthy Findings
Died or Sacrificed Moribund (Main
study) 0 0 0 0 0 0 0 0
Died or Sacrificed Moribund (TK
study) b 0 0 0 0 1 0 2 2
Body Weight (% c)
Day 8 29.54 g 22.23 g +0.37 +0.40 −2.13 +0.18 −11.2* +0.76
Day 15 29.09 g 22.61 g +0.96 +0.27 −1.17 +3.54 −6.39* +1.33
Day 22 30.16 g 22.85 g +0.23 −0.18 −0.70 +2.23 −7.86* +2.14
Day 29 29.61 g 23.58 g +1.82 −0.98 +1.28 −0.98 −5.27 +1.02
Food Consumption -- -- -- -- -- -- -- --
Water Consumption ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦
Clinical Observations d
Decreased motor activity -- -- -- -- 1 (2) -- 6 (21) 2 (9)
Rapid and shallow breathing -- -- -- -- -- 1 (1) 5 (14) 1 (1)
Hunched -- -- -- -- -- -- 5 (17) 2 (11)
Ruffled fur -- -- 4 (7) -- 3 (5) -- 10 (36) 1 (10)
Abbreviations: -- = No noteworthy findings; ♦ = Not conducted; NA = Not applicable; ND = Not defined; PEG = Polyethylene glycol; TK = Toxicokinetics; TPGS = d-α-tocopheryl polyethylene glycol 1000 succinate
* P ≤ 0.05, ** P ≤ 0.01 Dunnett’s Test All footnotes are available as table end notes.
Table 2.6.7.7A: Repeat-Dose Toxicity (Continued)
Document Control No.: 930050534 Study No.: DM09022
Daily Dose (mg/kg): (0) Control 50 150 500
Number of Animals:a M: 10 F: 10 M: 10 F: 10 M: 10 F: 10 M: 10 F: 10
Physical Examinations ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦
Ophthalmoscopy ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦
Electrocardiography ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦
Hematology
Hemoglobin (g/dL) 16.81 14.94 16.32 14.92 15.85* 15.09 15.36* 13.94
Hematocrit (%) 54.90 49.83 53.28 48.15 51.88* 48.14 50.87* 44.46*
Mean corpuscular hemoglobin (pg) 15.62 15.32 15.54 15.66 15.47 15.33 15.13* 14.98
Mean corpuscular volume (fL) 51.0 51.0 50.7 50.4 50.5 49.0* 50.0* 47.9*
Red blood cell count (106/μL) 10.75 9.767 10.511 9.535 10.253 9.84 10.16* 9.298
Serum Chemistry
Albumin (g/dL) 3.74 3.68 3.70 3.87 3.75 3.93 3.73 4.03*
Alkaline phosphatase (U/L) 76.6 98.7 74.8 114.5 80.5 116.5 88.6 137.6*
Chloride (mEq/L) 105.8 109 107.2 110.1 108.5* 109.5 110.5* 109.5
Potassium (mEq/L) 7.08 9.60 7.77* 10.0 7.35 10.03 7.30 10.85*
Sodium (mEq/L) 148.7 148.9 148.2 149.6 150.9 150 152.8* 150.4
Total bilirubin (mg/dL) 0.18 0.17 0.15 0.12 0.17 0.13 0.46* 0.23
Total cholesterol (mg/dL) 168.7 113.3 168.3 112.3 166.7 133.6 170.3 136.6*
Total protein (g/dL) 6.60 5.98 6.44 5.98 6.39 6.31 6.49 6.37*
Urinalysis ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦
Organ Weights (% e )
Liver 1.36894 g 1.10271 g −5.25 −3.60 +0.44 +11.5* +2.92 +13.3*
Gross Pathology -- -- -- -- -- -- -- --
Histopathology
Kidney - dilatation, tubule
Minimal 1 2 3 ♦ 4 ♦ 3 3
Mild 0 0 5 ♦ 2 ♦ 3 0
a In addition to the main study animals, additional groups of satellite animals (5 mice/sex [Group 1, control] and 20 mice/sex/group [Groups 2-4]) were used for TK evaluations.
b Early deaths of TK animals (Days 4 and 9: 500 mg/kg/day F, Day 8: 500 mg/kg/day M) were considered BMS-650032 related, clinical observations were not performed; however (Day 21: 150 mg/kg/day M) there was no evidence of gavage-related trauma.
Abbreviations: -- = No noteworthy findings; ♦ = Not conducted; NA = Not applicable; ND = Not defined; PEG = Polyethylene glycol; TK = Toxicokinetics; TPGS = d-α-tocopheryl polyethylene glycol 1000 succinate
* P ≤ 0.05, ** P ≤ 0.01 Dunnett’s Test All footnotes are available as table end notes.
c For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences).
d The number indicates the number of animals with the finding; the number in parentheses indicates the number of occurrences.
e Both absolute and relative weights differed from controls in the direction indicated. Number indicates percent differences for the absolute organ weights.
Abbreviations: -- = No noteworthy findings; ♦ = Not conducted; LLOQ = Lower limit of quantitation; ND = Not determined; PEG = Polyethylene glycol; TPGS = d-α-tocopheryl polyethylene glycol 1000 succinate
* P ≤ 0.05, ** P ≤ 0.01 Dunnett’s Test All footnotes are available as table end notes.
Table 2.6.7.7B: Repeat-Dose Toxicity
Report Title: One-Month Oral Toxicity Study in Rats Study No.: DM07024
Species/Strain: Rat/Crl:CD (SD) Duration of Dosing: 1 month Document Control No.: 930024094 Initial Age: ~7 weeks Duration of Post Dose: 2 weeks Location in Dossier: 4.2.3.2.2 Date of First Dose: 20 Method of Administration: Oral (gavage)
Vehicle/Formulation: 60% PEG-400 and
40% TPGS GLP Compliance: GLP with exception of analysis of liver samples for BMS-650032 concentrations.
Special Features: Liver BMS-650032 concentration measured approximately 24 h after last dose.
No-Observed-Adverse-Effect Level: 100 mg/kg/day
Daily Dose (mg/kg): (0) Control 30 100 600
Number of Animals: M: 15 F: 15 M: 15 F: 15 M: 15 F: 15 M: 15 F: 15
Toxicokinetics:
Cmax (μg/mL)
Day 1 ♦ ♦ 0.658 0.785 14.9 14.5 29.2 20.1
Day 28 ♦ ♦ 0.290 0.306 11.1 13.7 24.7 43.4
AUC(0-24h) (μg•h/mL)
Day 1 ♦ ♦ 2.65 4.73 129 108 291 262
Day 28 ♦ ♦ 1.88 1.34 83.2 98.2 227 371
Tissue Toxicokinetics Liver (μg/g) a
Day 28 ♦ ♦ 49.0 31.5 96.9 93.1 228 264
Plasma (μg/mL) a
Day 28 ♦ ♦ 0.00640 <LLOQ 0.00618 0.0188 0.371 3.74
Liver-to-Plasma Concentration Ratio b
Day 28 ♦ ♦ 7,656 ND 15,680 4,952 615 71