参考文献

[資料4.3: 301] Halliwell WH. Cationic amphiphilic drug-induced phospholipidosis. Toxicol Pathol.

1997;25(1):53-60.

[資料4.3: 302] Reasor MJ, Hastings KL, Ulrich RG. Drug-induced phospholipidosis: issues and future directions. Expert Opin Drug Saf. 2006;5(4):567-83.

[資料4.3: 303] Reasor MJ, Kacew S. Drug-induced phospholipidosis: are there functional consequences?

Exp Biol Med (Maywood). 2001;226(9):825-30.

[資料4.3: 304] Vora KA, Porter G, Peng R, Cui Y, Pryor K, Eiermann G, et al. Genetic ablation or pharmacological blockade of dipeptidyl peptidase IV does not impact T cell-dependent immune response. BMC Immunol. 2009;10(19):1-11.

[資料4.3: 305] White PC, Chamberlain-Shea H, de la Morena MT. Sitagliptin treatment of patients with type 2 diabetes does not affect CD4+ T-cell activation. J Diabetes Complications.

2010;24(3):209-13.

[資料4.3: 306] Haninec P, Dubovy P. Fine structure histochemical study of the distribution of dipeptidylpeptidase IV (DPP IV) in the meningeal lamellae of the rat. Experientia.

1988;44(8):708-10.

[資料4.3: 307] Barnes K, Kenny AJ, Turner AJ. Localization of aminopeptidase N and dipeptidyl peptidase IV in pig striatum and in neuronal and glial cell cultures. Eur J Neurosci.

1994;6(4):531-7.

[資料4.3: 308] Schnabel R, Bernstein HG, Luppa H, Lojda Z, Barth A. Aminopeptidases in the circumventricular organs of the mouse brain: a histochemical study. Neuroscience.

1992;47(2):431-8.

[資料4.3: 309] Alponti RF, Frezzatti R, Barone JM, Alegre Vde S, Silveira PF. Dipeptidyl peptidase IV in the hypothalamus and hippocampus of monosodium glutamate obese and food-deprived rats.

Metabolism. 2011;60(2):234-42.

[資料4.3: 310] Mentlein R. Dipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides.

Regul Pept. 1999;85(1):9-24.

[資料4.3: 311] Guieu R, Fenouillet E, Devaux C, Fajloun Z, Carrega L, Sabateir JM, et al. CD26 modulates nociception in mice via its dipeptidyl-peptidase IV activity. Behav Brain Res.

2006;166(2):230-5.

[資料4.3: 312] Hong W, Petell JK, Swank D, Sanford J, Hixson DC, Doyle D. Expression of dipeptidyl peptidase IV in rat tissues is mainly regulated at the mRNA levels. Exp Cell Res.

1989;182(1):256-66.

[資料4.3: 313] Bernstein HG, Schön E, Ansorge S, Röse I, Dorn A. Immunolocalization of dipeptidyl aminopeptidase (DAP IV) in the developing human brain. Int J Dev Neurosci.

1987;5(3):237-42.

[資料4.3: 314] Karl T, Hoffmann T, Pabst R, von Hörsten S. Extreme reduction of dipeptidyl peptidase IV activity in F344 rat substrains is associated with various behavioral differences. Physiol Behav. 2003;80:123-34.

[資料4.3: 315] Conarello SL, Li Z, Ronan J, Roy RS, Zhu L, Jiang G, et al. Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proc Natl Acad Sci USA.

2003;100(11):6825-30.

[資料4.3: 316] Marguet D, Baggio L, Kobayashi T, Bernard AM, Pierres M, Nielsen PF, et al. Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc Natl Acad Sci USA. 2000;97(12):6874-9.

[資料4.3: 317] EI Yacoubi M, Vaugeois JM, Marguet D, Sauze N, Guieu R, Costentin J, et al. Behavioral characterization of CD26 deficient mice in animal tests of anxiety and antidepressant-like activity. Behav Brain Res. 2006;171(2):279-85.

[資料4.3: 318] Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology.

2011;141(1):150-6.

[資料4.3: 319] Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Bourcier T, et al. Pancreatic Safety of Incretin-Based Drugs—FDA and EMA Assessment. N Engl J Med.

2014;370(9):794-7.

[資料4.3: 320] Merck. Position paper reviewing the nonclinical and clinical pancreatic safety of sitagliptin.

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[資料4.3: 321] Engel SS, Williams-Herman DE, Golm GT, Clay RJ, Machotka SV, Kaufman KD, et al.

Sitagliptin: review of preclinical and clinical data regarding incidence of pancreatitis. Int J Clin Pract. 2010;64(7): 984-90.

[資料4.3: 322] Aston-Mourney K, Subramanian SL, Zraika S, Samarasekera T, Meier DT, Goldstein LC, et al. One year of sitagliptin treatment protects against islet amyloid-associated β-cell loss and does not induce pancreatitis or pancreatic neoplasia in mice. Am J Physiol Endocrinol Metab. 2013;305(4):E475-84.

[資料4.3: 323] Matveyenko AV, Dry S, Cox HI, Moshtaghian A, Gurlo T, Galasso R, et al. Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide

transgenic rat model of type 2 diabetes: interactions with metformin. Diabetes.

2009;58(7):1604-15.

[資料4.3: 324] Chadwick KD, Fletcher AM, Parrula MC, Bonner-Weir S, Mangipudy RS, Janovitz E, et al.

Occurrence of Spontaneous Pancreatic Lesions in Normal and Diabetic Rats: A Potential Confounding Factor in the Nonclinical Assessment of GLP-1-Based Therapies. Diabetes.

2014;63(4):1303-14.

[資料4.3: 325] Curran PG, DeGroot LJ. The effect of hepatic enzyme-inducing drugs on thyroid hormones and the thyroid gland. Endocr Rev. 1991;12(2):135-50.

[資料4.3: 326] Capen CC. Toxic responses of the endocrine system. In: Klaassen CD, editor. Casarett and Doull's toxicology: the basic science of poisons. 6th ed. New York: McGraw Hill, 2001:p711-59.

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

No formal acute toxicity studies have been conducted. However, the toxicity after a single dose can be assessed from the repeat-dose oral toxicity studies in mice, rats, rabbits, dogs, and monkeys. See the tabulated study summaries from mice studies (1 to 1500 mg/kg/day), rat studies (2 to 750 mg/kg/day), rabbit studies (2-500 mg/kg/day), dog studies (2 to 75 mg/kg/day), and monkey studies (1 to 300 mg/kg/day) below.

2.6.7.6 反復投与毒性試験：重要な試験以外の試験

Test Article: Omarigliptin

Species/

Strain

Method of Adminis-tration (Vehicle/

Formulation)

Duration of

Dosing

Doses (mg/kg)

Gender and No.

per Group

NOAELa

(mg/kg) Noteworthy Findings

Study Number Mouse/

CRL:CD1 (ICR)

Oral gavage (0.5% [w/v]

methyl-cellulose in deionized water)

29 days 0, 10, 30, 100, 250, 750

5F &

5M/

control group 20F &

20M/

omari-gliptin groupsc

N/A Toxicokinetic Parameters (Study Week 5)d:

At 10, 30, 100, 250, and

750 mg/kg/day, respectively (sexes combined):

• AUC0-24 hr (μM·hr): 182, 492, 1610, 3090, and 6970

• C_max (μM): 24.8, 68.0, 175, 284, and 618

• Tmax (hr): 0.5, 1.0, 0.5, 0.5, and 0.5

TT # -6037 [資料4.2.3.2:

TT 6037]

Mouse/

CRL:CD1 (ICR)

Oral gavage (0.5% [w/v]

methyl-cellulose in deionized water)

29 days 0, 1, 5 5F &

5M/

control group 20F &

20M/

omari-gliptin groups

N/A Toxicokinetic Parameters (Sexes Combined) in Study Week 5:

At 5 mg/kg/day:

• AUC_{0-24 hr} (μM·hr): 67.9

• C_max (µM): 9.65

• T_max (hr): 1.0 At 1 mg/kg/day:

• AUC_{0-24 hr} (μM·hr): 14.6

• C_max (µM): 2.09

• T_max (hr): 0.50

TT # -1061 [資料4.2.3.2:

TT 1061]

2.6.7 毒性試験概要表

2.6.7.6 反復投与毒性試験：重要な試験以外の試験（続き）

Test Article: Omarigliptin

Species/

Strain

Method of Adminis-tration (Vehicle/

Formulation)

Duration of Dosing

Doses (mg/kg)

Gender and No.

per Group

NOAELa

(mg/kg) Noteworthy Findings

Study Number Mouse/

CRL:CD1 (ICR)

Oral gavage (0.5% [w/v]

methyl-cellulose in deionized water)

91 to 93 days 0, 30, 100, 250, 750, 1500b

12F and 12M per group

250 At ≥30 mg/kg/day:

Increases in serum urea nitrogen At ≥100 mg/kg/day:

Decreases in body weight gain, decreases in leukocytes, lymphocytes, decrease in neutrophils, eosinophils, monocytes. Increases in creatinine; decreases in glucose and triglycerides

At ≥250 mg/kg/day:

Decreases in platelets and basophils. Increases in phosphorus.

TT # -6036 [資料4.2.3.4.2:

TT 6036]

2.6.7.6 反復投与毒性試験：重要な試験以外の試験（続き）

Test Article: Omarigliptin

Species/

Strain

Method of Adminis-tration (Vehicle/

Formulation)

Duration of Dosing

Doses (mg/kg)

Gender and No.

per Group

NOAELa

(mg/kg) Noteworthy Findings

Study Number Mouse/

CRL:CD1 (ICR)

Oral gavage (0.5% [w/v]

methyl-cellulose in deionized water)

91 to 93 days 0, 30, 100, 250, 750, 1500b

12F and 12M per group

250 At ≥750 mg/kg/day:

Increases in aspartate

aminotransferase and alkaline aminotransferase. Gastric mucous degeneration, focal epithelial hyperplasia and cellular infiltration in the gallbladder (750 mg/kg/day only), seminiferous tubule degeneration in the testes (750 mg/kg/day only).

At 1500 mg/kg/day:

Mortality (early termination of dose group), body weight loss, physical signs (including decreased activity, recumbency, unsteady/abnormal gait, coldness to the touch, eyes closed/partially closed and slowed respiration).

Vacuolation consistent with phospholipidosis in multiple tissues. Mucous cell hypertrophy in the submandibular salivary gland

TT # -6036 [資料4.2.3.4.2:

TT 6036]

2.6.7 毒性試験概要表

2.6.7.6 反復投与毒性試験：重要な試験以外の試験（続き）

Test Article: Omarigliptin

Species/

Strain

Method of Adminis-tration (Vehicle/

Formulation)

Duration of

Dosing

Doses (mg/kg)

Gender and No.

per Group

NOAELa

(mg/kg) Noteworthy Findings

Study Number Rat/

Crl:CD(SD)

Oral gavage (0.5% [w/v]

methyl-cellulose in deionized water)

7 days 0, 10, 100, 750

5F/group 100 Physical signs at 750 mg/kg/day consisted of decreased activity, red discharge from the eyes and nose, and ptosis. An increase in body weight gain was observed at 750 mg/kg/day.

At 100 mg/kg/day, decreased serum glucose. Findings limited to the 750 mg/kg/day dose group included decreased activity, red discharge from the eyes and nose, ptosis. increased body weight gain, increased BUN and alkaline phosphatase. Additional changes limted to 750 mg/kg/day:

increased liver weight, hepatocellular vacuolation and single cell necrosis, and alveolar histiocytosis in the lung.

The AUC0-24, Cmax, and Tmax for omarigliptin at 10, 100, and

750 mg/kg/day on Study Day 7 were 519, 4068, and 15330 μM·hr; 47.7, 355, and 961 µM; and 1.4, 2.2, and 2.6 hr, respectively.

TT # -2559 [資料4.2.3.2:

TT 2559]

ドキュメント内 CTD 第 2 部 2.6 非臨床試験の概要文及び概要表毒性試験の概要文 MSD 株式会社 (ページ 55-186)

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

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