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

MSD 株式会社

レテルモビル 錠剤／注射剤 PAGE 1 NONCLINICALWRITTEN/TABULATED SUMMARIES 2.6.7 毒性試験概要表

TABLE OF CONTENTS

2.6.7.1 Toxicology: Overview ............................................................................... 3 2.6.7.2 Toxicokinetics: Overview of Toxicokinetics Studies ............................... 14 2.6.7.3 Toxicokinetics: Overview of Toxicokinetics Data.................................... 17 2.6.7.4 Toxicology: Drug Substance .................................................................... 22 2.6.7.5 Single-Dose Toxicity ................................................................................ 31 2.6.7.6 Repeat-Dose Toxicity: Non-Pivotal Studies ............................................. 33 2.6.7.7A Repeat-Dose Toxicity: Report Title: 13 Week Oral (Gavage)

Administration Toxicity Study in the Mouse (TT # -7854) .............................. 41 2.6.7.7B Repeat-Dose Toxicity: Report Title: Subchronic Oral Toxicity Study

in Rats (13 Weeks Administration by Gavage with a Recovery Period for 4 Weeks) (TT # -7818) ....................................................................................... 46

2.6.7.7C Repeat-Dose Toxicity: Report Title: 26 Week Oral (Gavage) Administration Toxicity Study in the Rat Followed by a 4 Week Treatment-Free Period (TT # -7855) ................................................................................. 58

2.6.7.7D Repeat-Dose Toxicity: Report Title: 28 Day Intravenous (Bolus) Administration Toxicity Study in The Rat Followed by a 2 Week Treatment-free Period (TT # -7858) ................................................................................. 62

2.6.7.7E Repeat-Dose Toxicity: Report Title: A 13-Week Oral Toxicity Study in Monkeys with a 4-Week Recovery Period (TT # -7821) .............................. 70

2.6.7.7F Repeat-Dose Toxicity: Report Title: 39 Week Oral (Gavage) Administration Toxicity Study in the Monkey Followed by a 6 Week Treatment-Free Period (TT # -7853)................................................................ 74

2.6.7.7G Repeat-Dose Toxicity: Report Title: 28-Day Intravenous (Bolus) Administration Toxicity Study in the Monkey Followed by a 2 Week Treatment-free Period (TT # -7859) ................................................................ 81

2.6.7.8A Genotoxicity – In Vitro: Report Title: Ames-Test Screening (TT # -5595) 92

2.6.7.8B Genotoxicity – In Vitro: Report Title: Salmonella/ Microsome Test Plate Incorporation and Preincubation Method (TT # -7822) ........................... 97

2.6.7.8C Genotoxicity – In Vitro: Report Title: Cytogenetic Screening with Chinese Hamster V79 Cells (TT # -5596) ...................................................... 102

2.6.7.8D Genotoxicity – In Vitro: Report Title: In Vitro Chromosome Aberration Test With Chinese Hamster V79 Cells (TT # -7823) .................... 107

2.6.7.9 Genotoxicity – In Vivo: Report Title: Micronucleus-Test on the Male Mouse (TT # -7824) ...................................................................................... 124

2.6.7.10 Carcinogenicity ...................................................................................... 127 2.6.7.11 Reproductive and Developmental Toxicity: Non-Pivotal Studies ........... 128 2.6.7.12A Reproductive and Developmental Toxicity (Fertility and Early Embryonic

Development to Implantation): Report Title: Study of Fertility and Early Embryonic Development in Rats after Oral Administration (TT # -7828) ...... 132

レテルモビル 錠剤／注射剤 PAGE 2 NONCLINICALWRITTEN/TABULATED SUMMARIES 2.6.7 毒性試験概要表

2.6.7.12B Reproductive and Developmental Toxicity (Fertility and Early Embryonic Development to Implantation): Report Title: Oral (Gavage) Study of Fertility and Early Embryonic Development in the Male Rat (TT # -7852) ................................................................................................. 137

2.6.7.12C Reproductive and Developmental Toxicity (Fertility and Early Embryonic Development to Implantation): Report Title: Oral Fertility and Toxicokinetic Study in Male Rats (TT # -7150)............................................. 145

2.6.7.12D Reproductive and Developmental Toxicity (Fertility and Early Embryonic Development to Implantation): Report Title: 13-Week Oral (Gavage) Administration Male Fertility Study in the Cynomolgus Monkey with an 8-Week Recovery Phase (TT # -7863) ............................................. 149

2.6.7.13A Reproductive and Developmental Toxicity (Effects on Embryo-Fetal Development): Report Title: Developmental Toxicity Study in Rats after Oral Administration (TT # -7825) ................................................................. 152

2.6.7.13B Reproductive and Developmental Toxicity (Effects on Embryo-Fetal Development): Report Title: Developmental Toxicity in Rabbits after Oral Administration (TT # -7830) ......................................................................... 157

2.6.7.14 Reproductive and Developmental Toxicity Report Title (Effects on Pre- and Postnatal Development, Including Maternal Function): Oral (Gavage) Study of Pre- and Postnatal Development in the Rat (TT # -7860) ................. 162

2.6.7.15 Studies in Juvenile Animals: Report Title: 2-Week Oral (Gavage) Administration Toxicity Study in the Juvenile Rat (TT # -7838) ................... 168

2.6.7.16 Local Tolerance ...................................................................................... 170 2.6.7.17 Other Toxicity Studies ............................................................................ 172

レテルモビル 錠剤／注射剤 PAGE 17 NONCLINICALWRITTEN/TABULATED SUMMARIES 2.6.7 毒性試験概要表

2.6.7.3 Toxicokinetics: Overview of Toxicokinetics Data

Test Article: Letermovir

Steady State AUC (nghr/mL)

Daily Dose (mg/kg)

Mice Rat Dog Monkey Rabbits Humans

Female Male Female Male Female Male Female Male Female

Oral Administration

10 (SW 4) 2950 a

10 (GD 17) 20082 b NA

10 (GD 6) 6109 c NA

17 (SW 26) 25270 d 25600 d

20 (SW 4) 60144 e 38321 e

20 (SW 13) 29196 f 18557 f

25 (GD 20) 6635 g

25 (SW 39) 6001 h 4200 h

30 (SW 4) 16863 a

30 (SW 12) NA 33200 i

30 (SW 13) 6630 j 4680 j

30 (SW 15) NA 4540 k

40 (SW 13) 61220 l 72280 l

45 (SW 2) 13068 m 32480 m

45 (GD 6) 92797 c NA

レテルモビル 錠剤／注射剤 PAGE 18 NONCLINICALWRITTEN/TABULATED SUMMARIES 2.6.7 毒性試験概要表

2.6.7.3 Toxicokinetics: Overview of Toxicokinetics Data (Continued) Test Article: Letermovir

Steady State AUC (nghr/mL)

Daily Dose (mg/kg)

Mice Rat Dog Monkey Rabbits Humans

Female Male Female Male Female Male Female Male Female

Oral Administration (Continued)

50 (GD 17) 258731 b NA

50 (SW 26) 275800 d 129600 d

60 (SW 4) 184589 e 144919 e

60 (SW 12) NA 163000 i

60 (SW 13) 118033 f 80628 f

NA 28100n

60 (SW 15) NA 19460 k

75 (SW 2) 81370 o 23250 o

75 (GD 20) 47355 g

80 (SD 1) 33146 p 46033 p

100 (SD 1) 564011 q NA

100 (SW 4) 68343 a

100 (SW 13) 367800 l 182100 l 74320 j 41440 j

100 (SW 39) 59040 h 33670 h

120 (SW 13) NA 96500 n

125 (SW 2) 108600 o 159000 o

レテルモビル 錠剤／注射剤 PAGE 19 NONCLINICALWRITTEN/TABULATED SUMMARIES 2.6.7 毒性試験概要表

2.6.7.3 Toxicokinetics: Overview of Toxicokinetics Data (Continued) Test Article: Letermovir

Steady State AUC (nghr/mL)

Daily Dose (mg/kg)

Mice Rat Dog Monkey Rabbits Humans

Female Male Female Male Female Male Female Male Female

Oral Administration (Continued)

150 (SD 1) NA p 21114 p

150 (SW 2) 62260 o 90920 o

150 (SW 26) 747200 d 568300 d

180 (SW 4) 780403 e 416809 e

180 (SW 12) NA 355000 i

180 (SW 13) 649235 f 329865 f

180 (SW 15) NA 57920 k

180 (GD 6) 225157 c NA

200 (SD 1) 1047785q NA

225 (GD 20) 170211 g

240 (SW 2) 482910 r

240 (SW 13) NA 211000 n

250 (SD 1) 36617 p 33529 p

250 (SW 2) 193460 o 279770 o 250 (SW13): Mice 300/250 (SW 13): Monkey

365600l 348900l 166080 j 195490 j

250/200(SW39) 149400 h 204900 h

レテルモビル 錠剤／注射剤 PAGE 20 NONCLINICALWRITTEN/TABULATED SUMMARIES 2.6.7 毒性試験概要表

2.6.7.3 Toxicokinetics: Overview of Toxicokinetics Data (Continued) Test Article: Letermovir

Steady State AUC (nghr/mL)

Daily Dose (mg/kg)

Mice Rat Dog Monkey Rabbits Humans

Female Male Female Male Female Male Female Male Female

Oral Administration (Continued)

250 (SD 17pc) 1095279b NA

500 (SD 1) 1986783q NA

1000 (SD 1) 2181454q NA

2000 (SD 1) 2278789q NA

Intravenous Administration

3 (SW 2) 3201 s 2461 s

10 (SW 2) 18849 s 15052 s

10 (SW 4) 28724 t 22515 t 15904 u 14355 u

30 (SD 1) 158496 v 104291 v NA 77296 w

30 (SW 2) 112194 s 74181 s

30 (SW 4) 150458 t 116934 t 108552 u 88970 u

50 (SD 1) 312414 v 239418 v

100 (SD 1) 1000943v 709147 v 565689 w NA

100 (SW 2) 347579 x 417413 x

100 (SW 4) 719446 t 646421 t 400725 u 435460 u

(footnotes on following page)

レテルモビル 錠剤／注射剤 PAGE 21 NONCLINICALWRITTEN/TABULATED SUMMARIES 2.6.7 毒性試験概要表

2.6.7.3 Toxicokinetics: Overview of Toxicokinetics Data (Continued) Test Article: Letermovir

SD = Study Day; SW = Study Week; PO = Oral; IV = Intravenous; pc = post coitum, NA = Not Applicable a TT # -7819. Male and female values combined. b TT # -7825 c TT # -7860 d TT # -7855 e TT # -7817 f TT # -7818 g TT # -7830 h TT # -7853. Due to body weight loss/reduced body weight gain and signs of poor body condition (particularly in females), the high dose level was

reduced from 250 to 200 mg/kg/day during Week 9. i TT # -7150 j TT # -7821. Due to clinical signs observed, the high dose level was reduced from 300 to 250 mg/kg/day beginning on Day 11. k TT # -7852 l TT # -7854 m TT # -7832 n TT # -7863 o TT # -7908 p TT # -7831. Each dose of letermovir used a different vehicle: 80 mg/kg letermovir in PEG400 (oral gavage), 150 mg/kg letermovir (dry substance) in a

gelatin capsule, or 250 mg/kg letermovir in Tylose® + 0.5 % Tween® 80 (oral gavage). q TT # -1010 r TT # -7829. Male and female values combined. s TT # -7856 t TT # -7858 u TT # -7859 v TT # -7840 w TT # -1135. For the 30 mg/kg dose: 7.5 mL/kg dosed at a rate of 5 mL/min and 4 min infusion time; for the 100 mg/kg dose: 25 mL/kg dosed at a rate of

5 mL/min and 15 min infusion time. x TT # -7857