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2.6.5 薬物動態試験概要表

中外製薬株式会社

タルセバ錠 2.6.5 薬物動態試験概要表

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略語一覧略語英語名和名 A549 Human non-small cell lung cancer

derived cell line A549 ヒト非小細胞肺癌株 A549細胞

AUC area under the concentration-time curve 濃度－時間曲線下面積 AUC0-last AUC from time 0 to tlast 最終測定時点までの AUC AUC0-24h AUC from time 0 to 24 h 投与後24時間までの AUC AUC0-inf AUC from time 0 to infinity 無限大時間まで外挿した AUC BLOQ below the limit of quantification 定量下限未満 Cmax maximum concentration 最高濃度 [14C] radioactive carbon-14 labeled 放射性炭素14標識 CL total clearance 全身クリアランス CL/F apparent total clearance 見かけの全身クリアランス CMC carboxymethylcellulose カルボキシメチルセルロース CYP cytochrome P450 チトクローム P450 CYP1A1 CYP1A1 isozyme CYP1A1分子種 CYP1A2 CYP1A2 isozyme CYP1A2分子種 CYP1B1 CYP1B1 isozyme CYP1B1分子種 CYP2C8 CYP2C8 isozyme CYP2C8分子種 CYP2C9 CYP2C9 isozyme CYP2C9分子種 CYP2C19 CYP2C19 isozyme CYP2C19分子種 CYP2D6 CYP2D6 isozyme CYP2D6分子種 CYP3A2 CYP3A2 isozyme CYP3A2分子種 CYP3A4 CYP3A4 isozyme CYP3A4分子種 CYP3A5 CYP3A5 isozyme CYP3A5分子種 CYP3A4/3A5 CYP3A4 and CYP3A5 isozyme CYP3A4及び CYP3A5分子種 F bioavailability バイオアベイラビリティー F344 Fischer 344 rat Fischer 344ラット h hour (s) 時間 HEC hydroxyethylcellulose ヒドロキシエチルセルロース HPLC-UV high performance liquid

chromatography-ultraviolet spectrometry

高速液体クロマトグラフィー紫外部

吸収分析法

HN5 human head and neck cancer derived cell line HN5

ヒト頭頚部癌株 HN5細胞

IC50 concentration required for 50% inhibition

50%阻害濃度

i.v. intravenous 静脈内 Ki inhibitory constant 阻害定数 LC-MS/MS HPLC-combined with tandem mass

spectrometry 高速液体クロマトグラフィータンデ

ム質量分析法 LLE liquid-liquid extraction 液-液抽出 M2 O-desmethyl metabolite of OSI-493 OSI-493の O-脱メチル体 M11 carboxylic acid metabolite of OSI-

420/413 OSI-420/413のカルボン酸体

M17 O-desmethyl metabolite of OSI-356 OSI-356の O-脱メチル体 MC methylcellulose メチルセルロース MDR-1 multidrug resistance protein-1 多剤耐性たん白-1 MRP2 multidrug resistance associated protein

2 多剤耐性関連たん白2


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略語英語名和名 MRT mean residence time 平均滞留時間 Nu/nu nude (mouse) ヌードマウス mRNA messenger ribonucleic acid メッセンジャーリボ核酸 OSI-356 metabolite OSI-356 代謝物 OSI-356 OSI-420 O-desmethyl metabolite OSI-420 O-脱メチル代謝物 OSI-420 OSI-413 O-desmethyl metabolite OSI-413 O-脱メチル代謝物 OSI-413 OSI-420/413 sum of desmethyl metabolites OSI-420

and OSI-413 O-脱メチル代謝物 OSI-420と OSI-413の合計

OSI-493 metabolite OSI-493 代謝物 OSI-493 OSI-774 erlotinib エルロチニブ OSI-943 di-O-desmetyl metabolite OSI-943 di-O-脱メチル代謝物 OSI-943 PK pharmacokinetics 薬物動態 p.o. oral (per os) 経口 QWBA quantitative whole-body

autoradiography 定量的全身オートラジオグラフィー

SBECD sulfobutyl ether β-cyclodextrin sodium (Captisol)

Captisol の別名

SD Sprague-Dawley (rat) SD（系）ラット t1/2 elimination half-life 消失半減期 TK toxicokinetics トキシコキネティクス tlast time for the last measurable

concentration 最終濃度測定時点

tmax time to reach maximum concentration 最高濃度到達時間 UGT UDP (uridine diphosphate) –

glucuronosyltransferase UDP-グルクロノシルトランスフェラ

ーゼ UGT1A1 UGT1A1 isozyme UGT1A1分子種 Vdss volume of distribution at steady state 定常状態の分布容積 Vz/F oral volume of distribution during the

apparent terminal phase 経口投与後の見かけの分布容積


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目次

頁

2.6.5 薬物動態試験概要表 ..................................................................................................... 5 2.6.5.1 薬物動態試験一覧表 .............................................................................................. 5 2.6.5.2 分析方法及びバリデーション試験 .................................................................... 12 2.6.5.3 薬物動態試験：単回投与後の吸収 .................................................................... 15 2.6.5.4 薬物動態試験：反復投与後の吸収 .................................................................... 28 2.6.5.5 薬物動態試験：分布 ............................................................................................ 38 2.6.5.6 薬物動態試験：たん白結合 ................................................................................ 47 2.6.5.7 薬物動態試験：妊娠又は授乳動物における試験 ............................................ 49 2.6.5.8 薬物動態試験：その他の分布試験 .................................................................... 52 2.6.5.9 薬物動態試験：In vivo における代謝................................................................. 53 2.6.5.10 薬物動態試験：In vitro における代謝................................................................ 58 2.6.5.11 薬物動態試験：推定代謝経路 ............................................................................ 64 2.6.5.12 薬物動態試験：薬物代謝酵素の誘導／阻害 .................................................... 65 2.6.5.13 薬物動態試験：累積排泄 .................................................................................... 73 2.6.5.14 薬物動態試験：胆汁中排泄 ................................................................................ 75 2.6.5.15 薬物動態試験：薬物相互作用 ............................................................................ 76 2.6.5.16 薬物動態試験：その他 ........................................................................................ 76


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2.6.5 薬物動態試験概要表

2.6.5.1 薬物動態試験一覧表 Test Article: Erlotinib hydrochloride

Type of Study Test System Method of Administration

Dose or Additional Conc.

Testing Facility Study Number Location in CTD

Absorption

Single-dose Absorption

Nu/nu Mouse p.o. 20, 100 mg/kg M20 153 (1010385) 4.2.2.2-1 Nu/nu Mouse p.o. 20, 100 mg/kg M20 154 (1010392) 4.2.2.2-2 Nu/nu Mouse p.o. 20, 100 mg/kg M20 155 (1010632) 4.2.2.2-3 Fischer 344 Rat p.o. 20, 100 mg/kg R20 319 (1010545) 4.2.2.2-4 Sprague-Dawley Rat p.o. 1, 5, 10 mg/kg a R 0200 b ( 086) 4.2.3.2-4 Beagle Dog p.o. 20 mg/kg a D20 313 (1006862) 4.2.2.2-6 Beagle Dog p.o. 2.5, 5, 15, 50 mg/kg a D 0197 b ( 087/ 115) 4.2.3.2-11 Beagle Dog p.o., i.v. i.v.: 0.5, 2, 7 mg/kg

p.o.: 0.5, 1, 2, (5) c, 10, 50 mg/kg

D 0008 (DM -358774-02) 4.2.2.2-5

Beagle Dog p.o., i.v. i.v.: 7 mg/kg p.o.: 15 mg/kg

D 0009 (DM -358774-11) 4.2.2.2-7

Beagle Dog p.o. 100, 200 mg/kg a

D20 239 b (959-003) 4.2.3.1-2

Cynomolgus Monkey p.o., i.v. i.v.: 2 mg/kg a p.o.: 50 mg/body a

P20 138 ( 1470) 4.2.2.2-8

:

a: Calculated as free base b: GLP Study c: PK parameters in 5 mg/kg group were not determined because of insufficient data.

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Test Article: Erlotinib hydrochloride




Absorption

Repeat-dose Absorption

Nu/nu Mouse p.o. 100 mg/kg/day M20 315 (1010633) 4.2.2.2-9 Nu/nu Mouse p.o. 100 mg/kg/day M20 316 (1010634) 4.2.2.2-10 Nu/nu Mouse (A549

Xenograft model) p.o. 100 mg/kg/day M20 148 (1010030) 4.2.2.2-11

Sprague-Dawley Rat p.o. 1, 5, 10 mg/kg/day a R 0200 b ( 086) 4.2.3.2-4 Beagle Dog p.o. 2.5, 5 (7.5), 15

mg/kg/day a D 0197 b ( 087/ 115) 4.2.3.2-11

Cynomolgus Monkey p.o. 12.5, 50 mg/kg a, b.i.d.

P 0154 ( -1241-22) 4.2.3.2-12

a: Calculated as free base b: GLP Study

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Distribution

Tissue Distribution Nu/nu Mouse p.o. [14C] 10 mg/kg M 0018

(DM -358774-016) 4.2.2.3-1

Sprague-Dawley and Lister-Hooded Rat

p.o. [14C] 5 mg/kg a

R20 318 (1010574) 4.2.2.3-2

Plasma Protein Binding

Nu/nu Mouse, Sprague-Dawley Rat, Beagle Dog, and Human Plasma

in vitro Erlotinib hydrochloride0.5, 1 μg/mL

I20 125 4.2.2.3-4

CD-1 Mouse, Sprague-Dawley Rat, Beagle Dog, and Human Plasma

in vitro OSI-420 0.5, 1 μg/mL

I 0015 (DM -358774-08)

4.2.2.3-5

a: Calculated as free base

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Study in Pregnant or Nursing Animals

Placental Transfer

BrlHan: WIST Rat p.o. [14C] 5 mg/kg a

ADM -0063 (B 0835)

4.2.2.3-3

Excretion Into Milk

BrlHan: WIST Rat p.o. [14C] 5 mg/kg a

ADM -0064 (B 0836)

4.2.2.5-2


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Metabolism

in vivo

Sprague-Dawley Rat p.o. [14C] 5 mg/kg a R 0021 4.2.2.4-7 Sprague-Dawley Rat p.o. [14C] 5 mg/kg a R 0167 4.2.2.4-6 Beagle Dog p.o. [14C] 5 mg/kg a D 0157

(DM -358774-36) 4.2.2.4-8

Beagle Dog p.o. [14C] 5 mg/kg a

D 0158 (DM -358774-39)

4.2.2.4-9

in vitro Rat, and Human Liver

Microsomes in vitro 10 μM

V 0014 4.2.2.4-1

Rat, Dog, and Human Liver Microsomes

in vitro 1 μM

V 0015 4.2.2.4-3

Rat and Human Liver Microsomes

in vitro [14C] 1, 100 μM V 0014 4.2.2.4-2

Rat and Human Liver Microsomes, Human Lymphoblastoid Cell

in vitro 1 μM

V 0013 (DM -358774-10)

4.2.2.4-4

Rat Liver and Lung Microsomes, Human Lymphoblastoid Cell

in vitro [14C] 1 μM V 0162 (DM -358774-25)

4.2.2.4-5

Human Liver Microsome, rhCYPs

in vitro [14C] 0.5-100 μM V 0216 (DM -358774-41)

5.3.2.2-5


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Induction/Inhibition of Drug-Metabolizing Enzymes

Inhibition

Human Liver Microsomes in vitro Erlotinib, OSI-420 0 – 100 μM

V 0160 (DM -358774-30)

5.3.2.2-8

Human Liver Microsomes in vitro Erlotinib, OSI-420 0 – 80 μM

V 0161 (DM -358774-31)

5.3.2.2-9

Expressed Human UGT1A1 and Human, Rat, and Dog Liver Microsomes

in vitro Erlotinib 0 – 250 μM

V20 117 4.2.2.6-1

Expressed Human UGT1A1 and Human, Rat, and Dog Liver Microsomes


V20 131 4.2.2.6-2

Human UGTs and Rat, Dog, Monkey, and Human Microsomes

in vitro OSI-420 0 – 125 μM

V20 133 4.2.2.6-3

Cynomolgus Monkey Liver Microsomes


V20 134 4.2.2.6-4

Induction

Human intestinal cell line and primary human hepatocyte


D 087 (1010720) 5.3.2.2-10

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Excretion Wistar Rat p.o., i.v. i.v.: [14C] 2.2 mg/kg

p.o.: [14C] 5.19 mg/kg R20 312 (1008502) 4.2.2.5-1

Beagle Dog p.o. [14C] 5 mg/kg a D 0157 (DM -358774-36)

4.2.2.4-8

Excretion into bile Sprague-Dawley Rat p.o. [14C] 5 mg/kg a R 0021 4.2.2.4-7 Other Studies none a: Calculated as free base

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2.6.5.2 分析方法及びバリデーション試験

表 2.6.5.2-1 Inter-assay Precision and Accuracy for Erlotinib and OSI-420 from Quality Control Samples in Rat Plasma

using HPLC-UV Method

Location in CTD: 4.2.3.2-4

Study No.: R 0200 ( 086)

Analyte QC Level Concentration Added

(μg/mL) Concentration Found

(μg/mL) Replicates Precision (%) Accuracy (%) Erlotinib Low 0.02 0.021 11 8.1 104.5

Low 0.04 0.039 1 N/A 97.5 Low 0.1 0.101 13 5.9 100.9 Medium 0.1 0.101 11 3.7 101.5 Medium 0.2 0.198 1 N/A 99.0 Medium 0.5 0.507 13 2.8 101.4 High 0.4 0.406 11 1.6 101.5 High 0.8 0.802 1 N/A 100.3 High 2.0 2.015 13 1.4 100.8

OSI-420 Low 0.02 0.020 11 12.5 100.5 Low 0.04 0.046 1 N/A 115.0 Low 0.1 0.102 13 8.1 102.0 Medium 0.1 0.102 11 4.7 102.3 Medium 0.2 0.188 1 N/A 94.0 Medium 0.5 0.509 13 2.2 101.9 High 0.4 0.409 11 1.9 102.3 High 0.8 0.806 1 N/A 100.8 High 2.0 2.022 13 1.6 101.1

N/A: Not applicable.

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表 2.6.5.2-2 Inter-assay Precision and Accuracy for Erlotinib and OSI-420 from Quality Control Samples in Dog Plasma

using HPLC-UV Method

Location in CTD: 4.2.3.2-11

Study No.: D 0197 ( 087/ 115)

Analyte QC Level Concentration Added

(μg/mL) Concentration Found

(μg/mL) Replicates Precision (%) Accuracy (%) Erlotinib Low 0.01 0.011 14 6.2 105.0

Low 0.05 0.054 5 3.3 108.8 Low 0.1 0.113 9 10.0 112.7 Medium 0.05 0.050 14 4.7 99.9 Medium 0.25 0.260 5 3.1 103.9 Medium 0.5 0.513 9 2.0 102.5 High 0.2 0.200 14 2.3 100.1 High 1.0 1.004 5 3.0 100.4 High 2.0 2.027 9 2.0 101.3

OSI-420 Low 0.01 0.010 13 10.7 102.3 Low 0.05 0.052 5 13.3 103.6 Low 0.1 0.100 9 12.5 100.3 Medium 0.05 0.050 14 8.7 100.1 Medium 0.25 0.252 5 5.4 100.7 Medium 0.5 0.502 9 4.3 100.4 High 0.2 0.202 14 3.0 101.0 High 1.0 1.021 5 5.2 102.1 High 2.0 2.091 9 12.9 104.5

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表 2.6.5.2-3 Analytical Methods and Validation Results (Overview)

Between-batch Dilution integrity Species Matrix

Sample preparation

Assay range (ng/mL)

LOQ (ng/mL)

Recovery (%) Precision

(%) Accuracy

(%) Precision

(%) Accuracy

(%)

Study No. (Location in

CTD) HPLC-UV

Dog Plasma LLE 10 – 1000 10 – 1000

10 10

98 – 99 90 – 103

5.6 – 7.9 4.7 – 6.1

97 – 108 94 – 101

2.7 – 3.6 2.2 – 5.9

100 – 101 100 – 103

Mouse a Plasma LLE NT NT NT 1.2 – 2.2 1.3 – 2.4

97 – 105 100 – 135

NT NT

Rat a Plasma LLE NT NT NT 0.54 – 5.7 0.64 – 5.4

97 – 107 101 – 106

NT NT

A 0032 (4.2.2.1-1)

HPLC-UV (Result from QC samples in long term toxicokinetic analysis)

Rat Plasma LLE 20 – 2000 20 – 2000

20 20

NT 1.4 – 8.1

1.6 – 12.5 97.5 – 104.594.0 – 115.0

NT NT R 0200

(4.2.3.2-4)

Dog Plasma LLE 10 – 2000 10 – 2000

10 10

NT 2.0 – 10.0 3.0 – 13.3

99.9 – 112.7100.1 – 104.5

NT NT D 0197

(4.2.3.2-11) LC-MS/MS

Mouse Plasma LLE 0.999 – 3000 0.987 – 987

0.999 0.987

76.5 – 91.4 78.0 – 85.1

3.8 – 8.8 3.4 – 7.4

102.8 – 112.093.4 – 108.0

5.2 5.2

99.0 94.2

A20 323 (4.2.2.1-2)

Rat Plasma LLE 1.00 – 3008.521.00 – 1003.54

1.00 1.00

87.2 – 100.883.9 – 89.5

2.1 – 12.2 2.5 – 9.2

92.0 – 114.894.2 – 104.6

1.3 – 3.9 1.0 – 4.5

86.8 – 101.798.6 – 103.8

A20 322 (4.2.2.1-3)

Rabbit Plasma LLE 2.01 – 3008.521.05 – 1052.03

2.01 1.05

100.5 – 106.190.3 – 92.5

1.5 – 9.8 2.1 – 13.5

100.1 – 108.898.7 – 108.2

5.1 4.7

117.2 97.4

A20 321 (4.2.2.1-4)

Dog Plasma LLE 1.00 – 2997.540.987 – 987.13

1.00 0.987

58.9 – 67.1 55.3 – 68.5

4.8 – 17.7 4.6 – 8.1

100.1 – 111.798.5 – 112.5

4.2 – 5.5 3.7 – 4.9

89.8 – 95.5 98.2 – 104.5

A20 156 (4.2.2.1-5)

Monkey Plasma LLE 1.00 – 3008.521.00 – 1003.54

1.00 1.00

90.0 – 101.195.0 – 109.0

2.1 – 10.8 2.4 – 8.4

86.5 – 108.492.0 – 107.0

0.7 – 1.3 0.6 – 1.2

112.8 – 113.8110.6 – 110.7

A20 320 (4.2.2.1-6)

Upper value: Erlotinib, lower value: OSI-420 LLE: Liquid-Liquid extraction LOQ: Limit of quantification NT: Not tested a: Results of cross validation study with calibration samples prepared in dog plasma

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2.6.5.3 薬物動態試験：単回投与後の吸収

表 2.6.5.3-1 Pharmacokinetics: Absorption After a Single Dose (Species Comparison)


Species Mouse (nu/nu)

Rat (SD)

Rat (F344)

Dog (Beagle)

Dog (Beagle)

Dog (Beagle)

Monkey (Cynomolgus)

Human (Japanese)

Study No. (Doc. No.)

M20 153 (1010385)

R 0200 R20 319 (1010545)

D20 313 (1006862)

D 0197 D 0008 P20 138 JO16564

Location in CTD 4.2.2.2-1 4.2.3.2-4 4.2.2.2-4 4.2.2.2-6 4.2.3.2-11 4.2.2.2-5 4.2.2.2-8 5.3.3.2-3 Gender (M/F) /No. of Animals

F27/group (3/point)

MF each 5/group

F6/group (3/point)

M4 MF each 4/group

MF 3-8/group M/3 Cancer patient 6

Feeding condition

Fed Not stated Fed Fed Not stated Not stated Fast Fed

Vehicle/ Formulation

CMC/Tween 80 0.5% MC CMC/Tween 80 CMC 0.5% MC 0.5% MC 6% Captisol Tablet

Dosing Route p.o. p.o. p.o. p.o. p.o. p.o. p.o. p.o. Dose (mg/kg) 20, 100 1, 5, 10

(as free base)20, 100 20

(as free base)2.5, 5, 15, 50 (as free base)

0.5, 1, 2, 10, 50

20.4 (50 mg/body,as free base)

ca. 2.5 (150 mg/body, as free base)

Matrix Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Analyte Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Assay method LC-MS/MS HPLC/UV LC-MS/MS LC-MS/MS HPLC/UV HPLC/UV LC-MS/MS LC-MS/MS PK parameter: tmax (h) 20 mg/kg;

0.5 100 mg/kg;

1.0

1 mg/kg; 1.60 (M) 1.25 (F)

5 mg/kg; 3.20 (M) 1.60 (F)

10 mg/kg; 3.40 (M) 3.60 (F)

20 mg/kg; 2.0

100 mg/kg; 11

1.5 2.5 mg/kg; 1.13 (M, F)

5 mg/kg; 1.88 (M, F)

15 mg/kg; 1.88 (M, F)

50 mg/kg; 8.88 (M, F)

0.5 mg/kg; 0.5 (M)

1 mg/kg; 0.5 (M)

2 mg/kg; 0.75 (M, F)

10 mg/kg; 1.0 (M)

50 mg/kg; 2.0 (M)

1.7 6.0

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表 2.6.5.3-1 Pharmacokinetics: Absorption After a Single Dose (Species Comparison) (続)


Rat (SD)

Rat (F344)

Dog (Beagle)

Dog (Beagle)

Dog (Beagle)

Monkey (Cynomolgus)

Human (Japanese)

Cmax (ng/mL) 20 mg/kg; 7230

100 mg/kg; 23500

1 mg/kg; 98.8 (M) 195 (F)

5 mg/kg; 857 (M) 1380 (F)

10 mg/kg; 2000 (M) 3010 (F)

20 mg/kg; 2150

100 mg/kg; 7800

3500 2.5 mg/kg; 407 (M, F)

5 mg/kg; 721 (M, F)

15 mg/kg; 2620 (M, F)

50 mg/kg; 5680 (M, F)

0.5 mg/kg; 76 (M)

1 mg/kg; 88 (M)

2 mg/kg; 346 (M, F)

10 mg/kg; 850 (M)

50 mg/kg; 4209 (M)

2642

958

AUC0-last (ng•h/mL) (* AUC0-inf)

20 mg/kg; 32300

100 mg/kg; 188000

1 mg/kg; 627 (M) 888 (F)

5 mg/kg; 9124 (M) 17066 (F)

10 mg/kg; 25669 (M)41811 (F)

20 mg/kg; 24600

100 mg/kg; 149000

27800* 2.5 mg/kg; 1428 (M, F)

5 mg/kg; 3468 (M, F)

15 mg/kg; 24947 (M, F)

50 mg/kg; 74344 (M, F)

0.5 mg/kg; 155 (M)*

1 mg/kg; 181 (M)*

2 mg/kg; 907 (M, F)*

10 mg/kg; 4792 (M)*

50 mg/kg; 32912 (M)*

12949

12845 (0 – 24 h)

t1/2 (h) 20 mg/kg; 3.6

100 mg/kg; 5.4

ND 20 mg/kg; 2.0

100 mg/kg; ND

2.7 (harmonic

mean)

ND 0.5 mg/kg; 1.2 (M)

1 mg/kg; 1.2 (M)

2 mg/kg; 1.3 (M, F)

10 mg/kg; 1.9 (M)

50 mg/kg; 2.1 (M)

2.3

25.9

ND: Not determined

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表 2.6.5.3-2 Pharmacokinetics: Absorption After a Single Dose (Mouse)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.2-1 Study No.: M20 153 ( 1010385)

Species: Nu/nu Mouse Nu/nu Mouse Gender (M/F)/No. of Animals: F/27 a F/27 a Feeding Condition: Fed Fed Vehicle/Formulation: CMC/Tween 80 b CMC/Tween 80 b Method of Administration: p.o. p.o. Dose (mg/kg): 20 c 100 d Sample (e.g., whole blood, plasma, serum): Plasma Plasma Assay: LC-MS/MS LC-MS/MS PK Parameters:

Analyte: Erlotinib Erlotinib tmax (h) 0.5 1.0 Cmax (ng/mL) 7230 23500 t1/2 (h) 3.6 5.4 AUC0-last (ng•h/mL) 32300 (0 – 8 h) 188000 (0 – 24 h) CL/F (mL/min/kg) 8.2 7.8 MRT (h) 5.1 10

Analyte: OSI-420/413 OSI-420/413 tmax (h) 2.0 2.0 Cmax (ng/mL) 900 3420 t1/2 (h) 3.7 8.2 AUC0-last (ng•h/mL) 5100 (0 – 8 h) 47700 (0 – 24 h) MRT (h) 5.7 12.6 OSI-420/413 – Erlotinib AUC0-last ratio (%) 15.8 25.4

a: 27 females per dose group/3 per time point. b: Carboxymethylcellulose / Tween 80. c: Equivalent to 18.3 mg/kg free base. d: Equivalent to 91.5 mg/kg free base.

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Species: Nu/nu Mouse Nu/nu Mouse Gender (M/F)/No. of Animals: F/27 a F/27 a Feeding Condition: Fed Fed Vehicle/Formulation: CMC / Tween 80 b CMC / Tween 80 b Method of Administration: p.o. p.o. Dose (mg/kg): 20 c 100 d Sample (e.g., whole blood, plasma, serum): Plasma Plasma Assay: LC-MS/MS LC-MS/MS PK Parameters: Analyte: Erlotinib Erlotinib

tmax (h) 1.0 0.5 Cmax (ng/mL) 11100 25400 t1/2 (h) 4.6 2.7 AUC0-last (ng•h /mL) 34600 (0 – 8 h) 203000 (0 – 24 h) CL/F (mL/min/kg) 7.0 8.2 MRT (h) 6.0 6.3

Analyte: OSI-420/413 OSI-420/413

tmax (h) 1.0 8.0 Cmax (ng/mL) 1840 4440 t1/2 (h) 9.5 3.1 AUC0-last (ng•h /mL) 6670 (0 – 8 h) 56800 (0 – 24 h) MRT (h) 12.4 7.8 OSI-420/413 – Erlotinib AUC0-last ratio (%) 19.3 28.0

a: 27 females per dose group/3 per time point. b: Carboxymethylcellulose / Tween 80. c: Equivalent to 18.3 mg/kg free base. d: Equivalent to 91.5 mg/kg free base.

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Species: Nu/nu Mouse Nu/nu Mouse Gender (M/F)/No. of Animals: F/27 a F/27 a Feeding Condition: Fed Fed Vehicle/Formulation: 6% Captisol 6% Captisol Method of Administration: p.o. p.o. Dose (mg/kg): 20 b 100 c Sample (e.g., whole blood, plasma, serum): Plasma Plasma Assay: LC-MS/MS LC-MS/MS PK Parameters: Analyte: Erlotinib Erlotinib

tmax (h) 0.5 1.0 Cmax (ng/mL) 9250 26800 AUC0-last (ng•h/mL) 36800 (0 – 16 h) 278000 (0 – 24 h) CL/F (mL/min/kg) 9.1 6.0 MRT (h) 2.7 6.5


tmax (h) 2.0 8.0 Cmax (ng/mL) 1860 6560 AUC0-last (ng•h/mL) 9860 (0 – 16 h) 93700 (0 – 24 h) MRT (h) 3.3 8.0 OSI-420/413 – Erlotinib AUC0-last ratio (%) 26.8 33.7

a: 27 females per dose group/3 per time point. b: Equivalent to 18.3 mg/kg free base. c: Equivalent to 91.5 mg/kg free base.

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表 2.6.5.3-5 Pharmacokinetics: Absorption After a Single Dose (Rat)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.2-4 Study No.: R20 319 ( 1010545)

Species: Rat a Rat a Gender (M/F)/No. of Animals: F/6 b F/6 b Feeding Condition: Fed Fed Vehicle/Formulation: CMC/Tween 80 c CMC/Tween 80 c Method of Administration: p.o. p.o. Dose (mg/kg): 20 d 100 e Sample (e.g., whole blood, plasma, serum): Plasma Plasma Assay: LC-MS/MS LC-MS/MS PK Parameters: Analyte: Erlotinib Erlotinib

tmax (h) 2.0 11 Cmax (ng/mL) 2150 7800 t1/2 (h) 2.0 NC AUC0-last (ng•h/mL) 24600 (0 – 24 h) 149000 (0 – 24 h) CL/F (mL/min/kg) 12.4 NC MRT (h) 6.7 NC


tmax (h) 8.0 11 Cmax (ng/mL) 557 2140 t1/2 (h) 2.5 NC AUC0-last (ng•h/mL) 6660 (0 – 24 h) 41300 (0 – 24 h) MRT (h) 7.1 NC OSI-420/413 – Erlotinib AUC0-last ratio (%) 27.1 27.7

NC: Not calculated due to a plateau in the plasma concentration-time profile. a: Fischer 344 Rat. b: 6 females per dose group/3 per time point c: Carboxymethylcellulose/Tween 80 d: Equivalent to 18.4 mg/kg free base. e: Equivalent to 91.5 mg/kg free base.

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表 2.6.5.3-6 Pharmacokinetics: Absorption After a Single Dose (Rat)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.3.2-4 Study No.: R 0200 ( 086)

Species: Rat a Rat a Rat a Rat a Rat a Rat a Gender (M/F)/No. of Animals: M/5 F/5 M/5 F/5 M/5 F/5 Feeding Condition: NS NS NS NS NS NS Vehicle/Formulation: 0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC Method of Administration: p.o. / Day 1 p.o. / Day 1 p.o. / Day 1 p.o. / Day 1 p.o. / Day 1 p.o. / Day 1 Dose (mg/kg): 1 b 1 b 5 b 5 b 10 b 10 b Sample (e.g., whole blood, plasma, serum): Plasma Plasma Plasma Plasma Plasma Plasma Assay: HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV PK Parameters: Analyte: Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib

Cmax (ng/mL) range 52 – 167 116 – 338 629 – 1233 1238 – 1610 1668 – 2378 2237 – 3302 AUC0-24h (ng•h/mL) c 627 (111) 888 (298) d 9124 (3375) 17066 (3433) 25669 (3730) 41811 (5502)

Analyte: OSI-420/413 OSI-420/413 OSI-420/413 OSI-420/413 OSI-420/413 OSI-420/413

Cmax (ng/mL) range BLOQ – 31 BLOQ – 53 154 – 215 123 – 185 392 – 556 275 – 417 AUC0-24h (ng•h/mL) c ND 63 (81) d 2386 (333) 2073 (350) 6362 (839) 5301 (745)

NS: Not stated. MC: Methylcellulose. ND: Not determined. a: Sprague-Dawley rats. b: Doses were calculated as free base. c: Mean value (standard deviation). d: n=4 Many 24-hour values were BLOQ and were assigned a value of 0 for AUC calculations.

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表 2.6.5.3-7 Pharmacokinetics: Absorption After a Single Dose (Dog)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.2-6 Study No.: D20 313 ( 1006862)

Species: Beagle Dog Beagle Dog Gender (M/F)/No. of Animals: M/4 M/4 Feeding Condition: Fed a Fed a Vehicle/Formulation: 0.2%CMC 0.5%HEC Method of Administration: p.o. p.o. Dose (mg/kg): 20 b 20 b Sample (e.g., whole blood, plasma, serum): Plasma Plasma Assay: LC-MS/MS LC-MS/MS PK Parameters: Analyte: Erlotinib Erlotinib

Cmax (ng/mL) 3500 3060 tmax (h) 1.5 1.1 AUC0-inf (ng•h /mL) 27800 24400 CL/F (mL/min/kg) 12.5 15.4 t1/2 (h) 2.7 c 2.5 c

Vz/F (L/kg) 3.0 3.3 MRT (h) 6.4 6.2


Cmax (ng/mL) 536 482 tmax (h) 3.3 4.5 AUC0-inf (ng•h /mL) 6920 6130 t1/2 (h) 3.4 c 3.1 c

MRT (h) 7.9 7.4 OSI-420/413 – Erlotinib AUC0-inf ratio (%) 25.0 25.8 0.2% CMC: 0.2% Carboxymethylcellulose and 0.1% Polysorbat 80. 0.5% HEC: 0.5% Hydroxyethylcellulose, 0.1% Polysorbat 80, 0.09%Nipagin and 0.01% Nipasol. a: Animals were fed 0.5 h before test-article administration. b: Doses were calculated as free base. c: Harmonic mean.

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Test Article: Erlotinib hydrochloride Location in CTD: 4.2.3.2-11 Study No.: D 0197 ( 087/ 115)

Species: Beagle Dog Beagle Dog Beagle Dog Beagle Dog Gender (M/F)/No. of Animals: M/4 + F/4 M/4 + F/4 M/4 + F/4 M/4 + F/4 Feeding Condition: NS NS NS NS Vehicle/Formulation: 0.5% MC 0.5% MC 0.5% MC 0.5% MC Method of Administration: p.o. / Day 1 p.o. / Day 1 p.o. / Day 1 p.o. / Day 1 Dose (mg/kg): 2.5 a 5 a 15 a 50 a Sample (e.g., whole blood, plasma, serum): Plasma Plasma Plasma Plasma Assay: HPLC-UV HPLC-UV HPLC-UV HPLC-UV

PK Parameters: Analyte: Erlotinib Erlotinib Erlotinib Erlotinib

Cmax (ng/mL) range 164 – 651 267 – 1200 431 – 3903 565 – 12559 AUC0-24h (ng•h/mL) b 1428 (656) 3468 (1532) 24947 (16042) 74344 (68967)

Analyte: OSI-420/413 OSI-420/413 OSI-420/413 OSI-420/413

Cmax (ng/mL) range 46 – 135 67 – 179 90 – 579 129 – 1491 AUC0-24h (ng•h/mL) b 578 (391) 735 (322) 4593 (2664) 12714 (9802)

NS: No stated. a: Doses were calculated as free base. b: Mean value (standard deviation)

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Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.2-5 Study No.: D 0008 ( DM -358774-02)

Species: Beagle Dog Beagle Dog Beagle Dog Beagle Dog Beagle Dog Beagle Dog Beagle Dog Beagle Dog Gender (M/F)/No. of Animals:

M/11 M/2 + F/2 M/3 + F/3 M/4 M/4 M/6 + F/2 M/4 M/3

Feeding Condition: NS NS NS NS NS NS NS NS Vehicle/Formulation: Varied a 35% SBECD 20% SBECD 0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC Method of Administration: i.v. i.v. i.v. p.o. p.o. p.o. p.o. p.o. Dose (mg/kg): 0.5 2 7 0.5 1 2 10 50 Sample (e.g., whole blood, plasma, serum):

Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma

Assay: HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV PK Parameters: Analyte: Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib

Cmax (ng/mL) c 272 (39) b 669 (255) b 4901 (1234) b 63 (22) 88 (33) 346 (107) 850 (663) 4209 (3760) tmax (h) c 0.083 0.083 0.083 0.75 (0.29) 0.50 (0.0) 0.75 (0.58) 1.0 (0.71) 2.0 (1.7) AUC0-inf (ng•h/mL) c 179 d 1035 (348) 7421 (4377) 155 f 181 (29) 907 (310) 4792 f 32912 (43015) CL or CL/F (mL/min/kg) c

48 d 35 (11) 19 (6) ND ND ND ND ND

t1/2 (h) e 0.64 d 1.2 1.3 1.2 f 1.2 1.3 1.9 f 2.1 Vdss (L/kg) c 2.5 d 3.4 (1.1) 1.8 (0.2) ND ND ND ND ND F% c, g N/A N/A N/A 87 f 51 (8) 88 (30) 45 f ND

N/A: Not applicable. NS: Not stated. SBECD: Sulfobutyl ether β-cyclodextrin. MC: Methylcellulose. ND: Not determined. a: DMSO/2 dogs, 40% SBECD/3 dogs, Glycerol Formyl/6 dogs. b: Cmax determined at 5-minute time point. c: Mean value (standard deviation). d: Mean of 6 animals. e: t1/2 was calculated as ln2/(mean value of kel). f: Mean of 2 animals. g: Calculated using 0.5 mg/kg i.v. data for 0.5 & 1 mg/kg p.o., 2 mg/kg i.v. data for 2 mg/kg p.o., 7 mg/kg i.v. data for 10 mg/kg p.o..

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Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.2-7 Study No.: D 0009 ( DM -358774-11)

Species: Beagle Dog Beagle Dog Beagle Dog Gender (M/F)/No. of Animals: M/3 + F/3 M/3 + F/3 M/3 + F/3 Feeding Condition: Fasted Fed NS Vehicle/Formulation: 0.5% MC 0.5% MC 35% SBECD Method of Administration: p.o. p.o. i.v. Dose (mg/kg): 15 15 7 Sample (e.g., whole blood, plasma, serum): Plasma Plasma Plasma Assay: HPLC-UV HPLC-UV HPLC-UV PK Parameters: Analyte: Erlotinib Erlotinib Erlotinib

Cmax (ng/mL) a 877 (605) 2339 (1010) 5931 (979) tmax (h) a 1.2 (0.7) 2.0 (2.9) 0.083 AUC0-inf (ng•h/mL) a 2651 (2117) 13841 (4064) b 9151 (2421) CL or CL/F (mL/min/kg) a ND ND 14 (3) Vdss (L/kg) a ND ND 2.0 (0.1) t1/2 (h) a 1.6 (0.4) 3.5 (1.0) b 2.0 (0.7) F% a 14 (11) 71 (21) b N/A

Analyte: OSI-420/413 OSI-420/413 OSI-420/413

Cmax (ng/mL) a 122 (71) 332 (74) 239 (34) tmax (h) a 1.4 (0.7) 3.3 (2.4) 2.3 (0.8) AUC0-inf (ng•h/mL) a 620 (484) 3907 c 1341 (114) b t1/2 (h) a 2.2 (0.7) 4.7 c 1.9 (0.6) b

SBECD: Sulfobutyl ether β-cyclodextrin. MC: Methylcellulose. NS: Not stated. N/A: Not applicable. ND: Not determined. a: Mean value (Standard deviation) b: n=5 c: n=2

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Test Article: Erlotinib hydrochloride Location in CTD: 4.2.3.1-2 Study No.: D20 239 ( 959-003)

Species: Beagle Dog Beagle Dog Beagle Dog Beagle Dog Gender (M/F)/No. of Animals: M/3 F/3 M/3 F/3 Feeding Condition: NS NS NS NS Vehicle/Formulation: 6% SBECD 6% SBECD 6% SBECD 6% SBECD Method of Administration: p.o. p.o. p.o. p.o. Dose (mg/kg): a 100 100 200 200 Sample (e.g., whole blood, plasma, serum):

Plasma Plasma Plasma Plasma

Assay: LC-MS/MS LC-MS/MS LC-MS/MS LC-MS/MS PK Parameters: Analyte: Erlotinib Erlotinib Erlotinib Erlotinib

Cmax (ng/mL) b 10500 (3990) 8120 (1760) 12500 (520) 7820 (1740) AUC0-inf (ng•h/mL) b 85700 (56100) 122000 (81400) 216000 (65800) 146000 (41800) CL/F (mL/min/kg) b 30.0 (25.8) 17.7 (9.03) 16.5 (5.52) 24.5 (8.10) t1/2 (h) b 1.62 (0.895) 2.64 (1.87) 2.04 (0.509) 2.93 (2.43) tmax (h) b 1.5 (0.866) 6.00 (5.29) 5.33 (2.31) 6.67 (4.62)


Cmax (ng/mL) b 1410 (367) 1540 (408) 2220 (182) 1830 (405) AUC0-inf(ng•h/mL) b 19600 (10800) 31700 (19200) 53900 (8900) 43400 (4410) t1/2 (h) b 3.23 (1.49) 1.93 (0.321) 2.79 (1.27) 2.04 (0.522) tmax (h) b 4.67 (3.06) 9.33 (4.62) 14.7 (8.33) 17.3 (11.5) OSI-420/413 – Erlotinib AUC0-inf ratio b 0.253 (0.0839) 0.266 (0.0494) 0.257 (0.0401) 0.314 (0.0872)

NS: Not stated. SBECD: Sulfobutyl ether β-cyclodextrin. a: Doses were calculated as free base. b: Mean value (standard deviation)

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表 2.6.5.3-12 Pharmacokinetics: Absorption After a Single Dose (Monkey)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.2-8 Study No.: P20 138 ( 1470)

Species: Cynomolgus Monkey Cynomolgus Monkey Cynomolgus Monkey Cynomolgus Monkey Gender (M/F)/No. of Animals: M/3 M/3 M/3 M/3 Feeding Condition: Fasted Overnight Fasted Overnight Fasted Overnight Fasted Overnight Vehicle/Formulation: Tablet 6% Captisol 6% Captisol 50% PEG 400 Method of Administration: p.o. p.o. i.v. i.v. Dose: a 50 mg (20.69 mg/kg) 50 mg (20.36 mg/kg) 2 mg/kg 2 mg/kg

Sample (e.g., whole blood, plasma, serum): Plasma Plasma Plasma Plasma Assay: LC-MS/MS LC-MS/MS LC-MS/MS LC-MS/MS PK Parameters: Analyte: Erlotinib Erlotinib Erlotinib Erlotinib

Cmax (ng/mL) b 1236 (456) 2642 (1074) 2216 (138) 1888 (195) tmax (h) b 2.3 (1.5) 1.7 (0.6) N/A N/A AUC0-inf (ng•h/mL) b 6447 (5368) 13092 (8985) 1545 (639) 1772 (633) AUC0-last (ng•h/mL) b 6326 (5438) 12949 (9100) 1538(639) 1767 (629) t1/2 (h) b 4.6 (4.8) 2.3 (0.7) 0.5 (0.2) 0.6 (0.2) CL or CL/F (mL/min/kg) b 82.2 (59.4) 32.8 (15.7) 25.2 (13.2) 20.6 (7.58) Vdss (mL/kg) b ND ND 930 (85) 1061 (34) F (%) Relative to i.v. 50% PEG 400 b 44.1 (45.1) 89.2 (84.7) N/A N/A F (%) Relative to i.v. 6% Captisol b 36.2 (15.2) 81.3 (27.9) N/A N/A


Cmax (ng/mL) b 785 (477) 1325 (592) 58 (41) 85 (70) tmax (h) b 2.3 (1.5) 1.7 (0.6) 1.0 (1.0) 1.0 (0.0) AUC0-inf (ng•h/mL) b 3271 (2549) 7810 (6950) 164 (156) 243 (237) AUC0-last (ng•h/mL) b 2929 (2088) 7727 (7016) 157(157) 236 (239) t1/2 (h) b 1.4 (0.6) 1.5 (0.3) 0.8 (0.1) 0.7 (0.05)

N/A: Not applicable. ND: Not determined. a: Doses were calculated as free base. b: Mean value (standard deviation)

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2.6.5.4 薬物動態試験：反復投与後の吸収

表 2.6.5.4-1 Pharmacokinetics: Absorption After Repeated Doses (Species Comparison)



Rat (SD)

Dog (Beagle)

Monkey (Cynomolgus)

Human (Japanese)

Study No. M20 315 M20 316

R 0200 D 0197 P 0154 JO16564

Location in CTD 4.2.2.2-9 4.2.2.2-10

4.2.3.2-4 4.2.3.2-11 4.2.3.2-12 5.3.3.2-3

Gender (M/F)/No. of Animals F12-15/ group (2-3/point)

MF each 4-5/ group MF each 4/ group MF each 2/ group 6 Cancer patient

Feeding condition Fed Not stated Not stated Not stated Fed Vehicle/Formulation 6% Captisol

CMC/Tween 80 0.5% MC 0.5% MC 0.5% MC Tablet

Method of Administration Once a day for 2 weeks

Once a day for 6 months

Once a day for 12 months

Twice a day for 7 days

Once a day for 21days

Dose (mg/kg/day) 100 1, 5, 10 (as free base)

2.5, 5→7.5, 15 (as free base)

25 (12.5 b.i.d.), 100 (50 b.i.d) (as free base)

ca. 2.5 (150 mg/body, as free base)

Matrix Plasma Plasma Plasma Plasma Plasma Analyte Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Assay method LC-MS/MS HPLC/UV HPLC/UV HPLC/UV LC-MS/MS PK parameters:

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表 2.6.5.4-1 Pharmacokinetics: Absorption After Repeated Doses (Species Comparison) (続)


Rat (SD)

Dog (Beagle)

Monkey (Cynomolgus)

Human (Japanese)

tmax (h) Last dosing day 6% Captisol

0.25 CMC/Tween 80

0.25

Day 176 1 mg/kg;

1.5 (M) 1.0 (F)

5 mg/kg; 1.3 (M) 1.0 (F)

10 mg/kg; 1.4 (M) 1.2 (F)

Day 183 2.5 mg/kg;

1.25 (M, F) 7.5 mg/kg;

1.63 (M, F) 15 mg/kg;

2.63 (M, F) Day 351 2.5 mg/kg;

1.13 (M, F) 7.5 mg/kg;

1.13 (M, F) 15 mg/kg;

1.00 (M, F)

Day 3 12.5 mg/kg b.i.d.;

1 (M, F) 50 mg/kg b.i.d.;

2 (M, F) Day 7 12.5 mg/kg b.i.d.;

2 (M, F) 50 mg/kg b.i.d.;

4 (M, F)

Last dosing day 1.8

Cmax (ng/mL) Last dosing day 6% Captisol

18500 CMC/Tween 80

10500

Day 176 1 mg/kg;

157 (M) 317 (F)

5 mg/kg; 1230 (M) 1940 (F)

10 mg/kg; 1890 (M) 2860 (F)

Day 183 2.5 mg/kg;

323 (M, F) 7.5 mg/kg;

1290 (M, F) 15 mg/kg;

1840 (M, F) Day 351 2.5 mg/kg;

270 (M, F) 7.5 mg/kg;

802 (M, F) 15 mg/kg;

2580 (M, F)


1100 (M, F) 50 mg/kg b.i.d.;

6900 (M, F) Day 7 12.5 mg/kg b.i.d.;

140 (M, F) 50 mg/kg b.i.d.;

6700 (M, F)

Last dosing day 2384

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表 2.6.5.4-1 Pharmacokinetics: Absorption After Repeated Doses (Species Comparison) (続)


Rat (SD)

Dog (Beagle)

Monkey (Cynomolgus)

Human (Japanese)

AUC0-24h (ng･h/mL) (* AUC0-last)

Last dosing day 6% Captisol

116000* CMC/Tween 80

88200*

Day 176 1 mg/kg;

1080 (M) 1900 (F)

5 mg/kg; 12400 (M) 22000 (F)

10 mg/kg; 21200 (M) 37000 (F)

Day 183 2.5 mg/kg;

1420 (M, F) 7.5 mg/kg;

6470 (M, F) 15 mg/kg;

14800 (M, F) Day 351 2.5 mg/kg;

854 (M, F) 7.5 mg/kg;

2390 (M, F) 15 mg/kg;

15000 (M, F)


2200 (M, F)* 50 mg/kg b.i.d.;

27300 (M, F)* Day 7 12.5 mg/kg b.i.d.;

360 (M, F)* 50 mg/kg b.i.d.;

33100 (M, F)*

Last dosing day 42679

t1/2 (h) Last dosing day 6% Captisol

2.5 CMC/Tween 80

8.0

Day 176 ND

Day 183 ND

Day 351

ND


1.7 (M, F) 50 mg/kg b.i.d.;

1.3 (M, F) Day 7 12.5 mg/kg b.i.d.;

ND 50 mg/kg b.i.d.;

ND

Last dosing day 27.2

ND：Not determined. In dog study, dose increased from 5 mg/kg to 7.5 mg/kg at day 50.

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表 2.6.5.4-2 Pharmacokinetics: Absorption After Repeated Doses (Mouse)


Species: Nu/nu Mouse Nu/nu Mouse Gender (M/F)/No. of Animals: F/15 a F/12 a Feeding Condition: Fed Fed Vehicle/Formulation: 6% Captisol 6% Captisol Method of Administration: p.o. / single b p.o. / repeated c

Dose (mg/kg/day): 100 d 100 d

Sample (e.g., whole blood, plasma, serum): Plasma Plasma Assay: LC-MS/MS LC-MS/MS PK Parameters: Analyte: Erlotinib Erlotinib

tmax (h) 0.25 0.25 Cmax (ng/mL) 22500 18500 t1/2 (h) e 1.8 2.5 AUC (ng•h/mL) 136000 (0 – 24 h) 116000 (0 – 12 h) CL/F (mL/min/kg) 12.2 13.6 MRT (h) 4.1 4.2

Analyte: OSI-420/413 OSI-420/413 tmax (h) 1.0 1.0 Cmax (ng/mL) 7030 9010 t1/2 (h) e 2.3 1.7 AUC (ng•h/mL) 76400 (0 – 24 h) 79500 (0 – 24 h) MRT (h) 5.9 4.9

a: 15 or 12 females per dose group/2 or 3 animals per time point. b: Single dose after 2 weeks once daily administration of vehicle. c: Repeated dose once daily over 2 weeks. d: Equivalent to 91.5 mg/kg free base. e: Rough estimates.

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Species: Nu/nu Mouse Nu/nu Mouse Gender (M/F)/No. of Animals: F/15 a F/15 a Feeding Condition: Fed Fed Vehicle/Formulation: CMC / Tween 80 b CMC / Tween 80 b

Method of Administration: p.o. / single c p.o. / repeated d

Dose (mg/kg/day): 100 e 100 e

Sample (e.g., whole blood, plasma, serum): Plasma Plasma Assay: LC-MS/MS LC-MS/MS PK Parameters: Analyte: Erlotinib Erlotinib

tmax (h) 6.0 0.25 Cmax (ng/mL) 11900 10500 t1/2 (h) f 4.8 8.0 AUC (ng•h/mL) 109000 (0 – 12 h) 88200 (0 – 12 h) CL/F (mL/min/kg) 11.6 13.0 MRT (h) 8.8 11

Analyte: OSI-420/413 OSI-420/413 tmax (h) 6.0 6.0 Cmax (ng/mL) 7500 7250 t1/2 (h) f 1.3 1.2 AUC (ng•h/mL) 87100 (0 – 24 h) 97100 (0 – 24 h) MRT (h) 7.3 7.7

a: 15 females per dose group/2 or 3 animals per time point. b: Carboxymethylcellulose / Tween 80. c: Single dose after 2 weeks once daily administration of vehicle. d: Repeated dose once daily over 2 weeks. e: Equivalent to 91.5 mg/kg free base. f: Rough estimates.

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Species: Nu/nu Mouse a Nu/nu Mouse a Gender (M/F)/No. of Animals: F/18 b F/18 b Feeding Condition: Fed Fed Vehicle/Formulation: CMC / Tween 80 c CMC / Tween 80 c

Method of Administration: p.o. / single d p.o. / repeated e

Dose (mg/kg/day): 100 f 100 f Sample (e.g., whole blood, plasma, serum): Plasma Plasma Assay: LC-MS/MS LC-MS/MS PK Parameters: Analyte: Erlotinib Erlotinib

tmax (h) 1.0 0.25 Cmax (ng/mL) 18800 12000 t1/2 (h) g 8.6 4.2 AUC (ng•h/mL) 177000 (0 – 24 h) 129000 (0 – 24 h) CL/F (mL/min/kg) h 8.62 11.7 MRT (h) 6.6 8.2

Analyte: OSI-420/413 OSI-420/413 tmax (h) 1.0 12 Cmax (ng/mL) 5360 5150 t1/2 (h) g 1.4 2.2 AUC (ng•h/mL) 79600 (0 – 24 h) 76100 (0 – 24 h) MRT (h) 8.2 9.2

a: A549 xenograft model b: 18 females per dose group/3 animals per time point. c: Carboxymethylcellulose / Tween 80 d: Single dose after 3 weeks once daily administration of vehicle. e: Repeated dose once daily over 3 weeks. f: Equivalent to 91.5 mg/kg free base. g: Rough estimates. h: calculated using a dose based on free base.

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表 2.6.5.4-5 Pharmacokinetics: Absorption After Repeated Doses (Rat)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.3.2-4 Study No.: R 0200 ( 086)

Species: Rat a Rat a Rat a Rat a Rat a Rat a

Gender (M/F)/No. of Animals: M/4 F/5 M/4 F/5 M/5 F/5 Feeding Condition: NS NS NS NS NS NS Vehicle/Formulation: 0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC Method of Administration: p.o. / Day 176 p.o. / Day 176 p.o. / Day 176 p.o. / Day 176 p.o. / Day 176 p.o. / Day 176Dose (mg/kg/day) b: 1 1 5 5 10 10

Sample (e.g., whole blood, plasma, serum): Plasma Plasma Plasma Plasma Plasma Plasma Assay: HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV PK Parameters: Analyte: Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib

Cmax (ng/mL) range 72 – 244 181 – 428 687 – 1967 1517 – 2289 1687 – 2154 1756 – 3391 AUC0-24h (ng•h/mL) c 1075 (414) 1903 (545) 12375 (6022) 22043(4765) 21174 (5681) 37036 (7974)

Analyte: OSI-420/413 OSI-420/413 OSI-420/413 OSI-420/413 OSI-420/413 OSI-420/413

Cmax (ng/mL) range BLOQ – 45 BLOQ – 32 216 – 381 178 – 234 358 – 487 294 – 444 AUC0-24h (ng•h/mL) c ND 51 (56) 3543 (1299) 2609 (313) 6270 (772) 5899 (838)

NS: Not stated. MC: Methylcellulose. ND: Not determined. a: Sprague-Dawley rats. b: Doses were calculated as free base. c: Mean value (standard deviation)

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表 2.6.5.4-6 Pharmacokinetics: Absorption After Repeated Doses (Dog)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.3.2-11 Study No.: D 0197 ( 087/ 115)

Species: Beagle Dog Beagle Dog Beagle Dog Beagle Dog Beagle Dog Beagle Dog Beagle Dog Beagle Dog Beagle Dog Gender (M/F)/

No. of Animals:M/4 + F/4 M/4 + F/4 M/4 + F/4 M/4 + F/4 M/4 + F/4 M/4 + F/4 M/4 + F/4 M/4 + F/4 M/4 + F/4

Feeding Condition:

NS NS NS NS NS NS NS NS NS

Vehicle/ Formulation:

0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC

Method of Administration:

p.o. / Day 29

p.o. / Day 29

p.o. / Day 50

p.o. / Day 183

p.o. / Day 183

p.o. / Day 183

p.o. / Day 351

p.o. / Day 351

p.o. / Day 351

Dose (mg/kg/day) a:

5 15 7.5 b 2.5 7.5 b 15 2.5 7.5 b 15

Sample (e.g., whole blood,

plasma, serum):

Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma

Assay: HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV PK Parameters: Analyte: Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib

Cmax (ng/mL) range

289 – 976 244 – 5342 95 – 2720 227 – 439 162 – 2802 324 – 4739 112 – 647 176 – 1294 1839 – 3383

AUC0-24h c (ng•h/mL)

3129 (2134) 22194 (15539)

6942 (2644) 1415 (438) 6474 (3485) 14764 (13692)

854 (496) 2385 (944) 15006 (8448)

MC: Methylcellulose. NS: Not Stated. a: Doses were calculated as free base. b: Dose increased from 5.0 to 7.5 mg/kg on Day 50. c: Mean value (standard deviation)

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表 2.6.5.4-6 Pharmacokinetics: Absorption After Repeated Doses (Dog) (続)

Species: Beagle Dog Beagle Dog Beagle Dog Beagle Dog Beagle Dog Beagle Dog Beagle Dog Beagle Dog Beagle Dog Gender (M/F)/

No. of Animals:M/4 + F/4 M/4 + F/4 M/4 + F/4 M/4 + F/4 M/4 + F/4 M/4 + F/4 M/4 + F/4 M/4 + F/4 M/4 + F/4

Feeding Condition:

NS NS NS NS NS NS NS NS NS

Vehicle/ Formulation:

0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC

Method of Administration:

p.o. / Day 29

p.o. / Day 29

p.o. / Day 50

p.o. / Day 183

p.o. / Day 183

p.o. / Day 183

p.o. / Day 351

p.o. / Day 351

p.o. / Day 351

Dose (mg/kg/day) a:

5 15 7.5 b 2.5 7.5 b 15 2.5 7.5 b 15

Sample (e.g., whole blood,

plasma, serum):

Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma

Assay: HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV PK Parameters: Analyte: OSI-420/413 OSI-420/413 OSI-420/413 OSI-420/413 OSI-420/413 OSI-420/413 OSI-420/413 OSI-420/413 OSI-420/413

Cmax (ng/mL) range

56 – 179 52 – 682 191 – 318 26 – 62 49 – 332 62 – 714 14 – 62 64 – 225 339 – 707

AUC0-24h c (ng•h/mL)

873 (771) 4930 (3138) 2267 (529) 297 (122) 1901 (1055) 3402 (3000) 150 (76) 841 (324) 4288 (1922)

MC: Methylcellulose. NS: Not Stated. a: Doses were calculated as free base. b: Dose increased from 5.0 to 7.5 mg/kg on Day 50. c: Mean value (standard deviation)

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表 2.6.5.4-7 Pharmacokinetics: Absorption After Repeated Doses (Monkey)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.3.2-12 Study No.: P 0154 ( -1241-22)

Species: Cynomolgus

Monkey Cynomolgus Monkey

Cynomolgus Monkey

Cynomolgus Monkey

Cynomolgus Monkey

Cynomolgus Monkey

Gender (M/F)/No. of Animals: M/2 + F/2 M/2 + F/2 M/2 + F/2 M/2 + F/2 M/2 + F/2 M/2 + F/2 Feeding Condition: NS NS NS NS NS NS Vehicle/Formulation: 0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC 0.5% MC Method of Administration: p.o. / Day 1 p.o. / Day 3 p.o. / Day 7 p.o. / Day 1 p.o. / Day 3 p.o. / Day 7 Dose (mg/kg/day) a: 25 (12.5 b.i.d.) 25 (12.5 b.i.d.) 25 (12.5 b.i.d.) 100 (50 b.i.d.) 100 (50 b.i.d.) 100 (50 b.i.d.) Sample (e.g., whole blood, plasma, serum): Plasma Plasma Plasma Plasma Plasma Plasma Assay: HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV HPLC-UV PK Parameters: Analyte: Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib

Cmax (ng/mL) b 1600 (400) 1100 (500) 140 (70.0) 4200 (1100) 6900 (1800) 6700 (1900) tmax (h) b 3 (2) 1 (1) 2 (1) 4 (0) 2 (1) 4 (1) AUC0-last (ng•h/mL) b 6600 (1900) 2200 (2000) 360 (350) 23900 (6200) 27300 (25500) 33100 (11300) t1/2 (h) b 1.3 c 1.7 c ND 1.3 (0.3) 1.3 (0.7) d ND

NS: Not stated. ND: Not determined. MC: Methylcellulose. a: Doses were calculated as free base. b: Mean value (standard deviation) c: n=2 d: n=3

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2.6.5.5 薬物動態試験：分布

表 2.6.5.5-1 Pharmacokinetics: Organ Distribution (Mouse)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.3-1 Study No.: M 0018 ( DM -358774-016) Species: Mouse (nu/nu) Gender (M/F)/No. of Animals: F/1 per time point a Feeding Condition: Fed Vehicle/Formulation: DMSO:P105 (1:9) Method of Administration: p.o. Dose (mg/kg): 10 Radionuclide: 14C Specific Activity: 121.03 μCi/mg Analyte/Assay: [14C] Erlotinib / QWBA (autoradioluminography) Sampling Times: 1, 2, 4, 8, 24, 48, 96, and 168 hours

Ct (1 hour) Last time point Tissues/Organs conc. (nCi/g) b T/P c conc. (nCi/g) b T/P d Time (h) AUC (nCi•h/g) t1/2 (h) HN5 Tumor-Bearing Mice Alimentary Tract Contents

Cecum 2063 ± 103 25.5 21 ± 13 NC 24 NS NS Colon 808 ± 47 9.98 450 ± 48 NC 24 NS NS Intestine 2405 ± 519 29.7 16 ± 4 NC 24 NS NS Stomach 19234 ± 2229 237 944 ± 38 NC 8 NS NS

Blood Myocardium 87 ± 5 1.07 37 ± 2 0.949 4 145 2.7 Vessel (artery or vein) 81 ± 8 1.00 39 ± 1 1.00 4 147 3.2

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表 2.6.5.5-1 Pharmacokinetics: Organ Distribution (Mouse) (続)

Ct (1 hour) Last time point Tissues/Organs conc. (nCi/g) b T/P c conc. (nCi/g) b T/P d Time (h) AUC (nCi•h/g) t1/2 (h) Brain

Cerebellum 12 ± 2 0.148 6 ± 2 0.133 2 NS NS Cerebrum 12 ± 1 0.148 6 ± 2 0.133 2 NS NS Pituitary 65 ± 13 0.802 42 ± 7 0.933 2 NS NS Spinal cord 16 ± 2 0.198 8 ± 2 0.178 2 NS NS

Glands Adrenal 126 ± 16 1.56 70 ± 6 1.79 4 218 2.0 Brown adipose 94 ± 9 1.16 52 ± 3 1.33 4 184 3.9 Lacrimal 111 ± 26 1.37 62 ± 2 1.38 2 NS NS Pancreas 102 ± 8 1.26 57 ± 4 1.46 4 198 4.1 Salivary 86 ± 10 1.06 32 ± 4 0.821 4 138 2.4

Other Tissues Adipose 83 ± 8 1.02 57 ± 10 1.27 2 NS NS Kidney cortex 162 ± 13 2.00 16 ± 2 NC 8 544 2.1 Liver 277 ± 14 3.42 13 ± 2 NC 24 1408 5.4 Lung 90 ± 5 1.11 42 ± 6 1.08 4 165 3.0 Muscle 38 ± 4 0.469 21 ± 3 0.538 4 126 2.5 Myocardium 83 ± 4 1.02 38 ± 3 0.974 4 146 3.0 Nasal mucosa 114 ± 14 1.41 39 ± 15 1.00 4 NS NS Spleen 71 ± 7 0.877 7 ± 3 NC 8 188 2.3 Tumor 59 ± 6 0.728 11 ± 4 NC 8 179 3.1

Non-Tumor-Bearing Mice Alimentary Tract Contents

Cecum 5524 ± 779 81.2 9 ± 1 NC 24 NS NS Colon 788 ± 179 11.6 10 ± 2 NC 24 NS NS Intestine 5542 ± 857 81.5 10 ± 2 NC 24 NS NS Stomach 3149 ± 562 46.3 13 ± 2 NC 24 NS NS

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表 2.6.5.5-1 Pharmacokinetics: Organ Distribution (Mouse) (続)

Ct (1 hour) Last time point Tissues/Organs conc. (nCi/g) b T/P c conc. (nCi/g) b T/P d Time (h) AUC (nCi•h/g) t1/2 (h) Blood

Myocardium 66 ± 7 0.971 34 ± 3 0.971 4 157 3.0 Vessel (artery or vein) 68 ± 7 1.00 35 ± 2 1.00 4 153 3.1

Brain Cerebellum 11 ± 2 0.162 8 ± 2 0.143 2 NS NS Cerebrum 10 ± 1 0.147 7 ± 1 0.125 2 NS NS Pituitary 52 ± 7 0.765 45 ± 7 0.804 2 NS NS Spinal cord 11 ± 1 0.162 7 ± 2 0.125 2 NS NS

Glands Adrenal 90 ± 6 1.32 43 ± 2 1.23 4 187 2.9 Brown adipose 81 ± 7 1.19 46 ± 4 1.31 4 186 3.7 Lacrimal 83 ± 9 1.22 83 ± 9 1.22 1 NS NS Pancreas 80 ± 4 1.18 38 ± 5 1.09 4 174 2.8 Salivary 57 ± 12 0.838 28 ± 2 0.800 4 136 2.8

Other Adipose 65 ± 7 0.956 61 ± 9 1.09 2 NS NS Bile 1225 ± 189 18.0 1709 ± 82 NC 8 NS NS Kidney cortex 126 ± 23 1.85 11 ± 2 NC 24 742 6.6 Liver 221 ± 17 3.25 14 ± 3 NC 24 1278 5.8 Lung 70 ± 6 1.03 32 ± 4 0.914 4 157 2.6 Muscle 30 ± 2 0.441 18 ± 3 0.514 4 70 4.1 Myocardium 62 ± 7 0.912 34 ± 3 0.971 4 152 3.3 Spleen 52 ± 7 0.765 12 ± 7 NC 8 200 3.3

NC: Not calculated, no corresponding last time point for blood vessel data. NS: Not stated. a: 16 (8 tumor-bearing and 8 non-tumor-bearing) female Nude mice. b: Values represent the mean ± standard deviation of all measurements (3 to 5 times measurement using same sectioning or different sectioning). c: Values represent Tissue/Blood Ratio at one-hour time point. d: Values represent Tissue/Blood Ratio at corresponding time point.

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表 2.6.5.5-2 Pharmacokinetics: Organ Distribution (Rat)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.3-2 Study No.: R20 318 ( 1010574) Species: Rat (Sprague-Dawley) Gender (M/F)/Number of animals: M/2 per time point Feeding Condition: Fed Vehicle/Formulation: 0.5% HEC Method of Administration: p.o. Dose (mg/kg): 5 (calculated as free base) Radionuclide: 14C Specific Activity: 4.47 MBq/mg Analyte/Assay: [14C] Erlotinib / QWBA (autoradioluminography) Sampling Times: 1, 4, 8, 24, and 72 hours

Tissue concentration of radioactivity (μg equiv./g) (mean values) Tissue/plasma ratio

Tissues/Organs 1 h 4 h 8 h 24 h 72 h 1 h 24 h t1/2 (h) AUC c (μg equiv.•h/g)

Plasma a 0.930 0.806 0.642 0.011 ND 1.00 1.00 NC 8.43 Blood a 0.982 1.04 0.947 0.035 0.033 1.06 3.29 NC 11.9 (13.6) Blood 1.19 1.16 0.819 BLOQ BLOQ 1.24 NC NC NC Aorta 1.77 2.26 1.78 BLOQ BLOQ 1.90 NC NC NC Mandibular lymph nodes 0.978 1.16 1.03 BLOQ BLOQ 1.05 NC NC NC Kidney cortex 3.78 b 5.18 3.62 0.090 0.032 4.10 8.33 NC 48.0 (50.7) Kidney medulla 2.83 4.00 2.51 0.015 BLOQ 3.32 2.37 d NC 32.2 Liver 5.73 b 6.60 4.50 0.406 0.121 6.19 38.4 NC 70.5 (81.8) Brain 0.107 0.140 0.087 BLOQ BLOQ 0.114 NC NC NC Choroid plexus 0.519 0.590 0.417 BLOQ BLOQ 0.562 NC NC NC Meninges 0.247 0.320 0.131 BLOQ BLOQ 0.278 NC NC NC Pineal body 0.886 1.29 1.02 NS BLOQ 1.17 NS NC NC Spinal cord 0.128 b 0.150 0.108 BLOQ BLOQ 0.131 NC NC NC Adrenal cortex 3.80 5.11 4.23 0.343 0.113 4.16 34.0 NC 58.6 (68.6) Adrenal medulla 2.70 3.86 2.59 0.067 0.063 2.87 6.29 NC 35.0 (38.1) Pituitary 1.32 1.68 1.16 BLOQ BLOQ 1.43 NC NC NC

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表 2.6.5.5-2 Pharmacokinetics: Organ Distribution (Rat) (続)

Tissue concentration of radioactivity (μg equiv./g) (mean values) Tissue/plasma ratio Tissues/Organs 1 h 4 h 8 h 24 h 72 h 1 h 24 h t1/2 (h)

AUC c (μg equiv.•h/g)

Thymus 0.858 1.11 0.723 BLOQ BLOQ 0.930 NC NC NC Thyroid 1.72 1.89 1.25 0.055 BLOQ 1.87 12.2 d NC 18.6 Exorbital lachrymal gland 1.48 2.21 1.33 BLOQ BLOQ 1.60 NC NC NC Harderian gland 1.79 2.21 1.43 0.012 BLOQ 1.94 1.86 d NC 18.8 Intra-orbital lachrymal gland 1.34 2.19 1.26 0.012 BLOQ 1.44 2.73 d NC 17.0 Salivary glands 1.42 1.94 1.18 BLOQ BLOQ 1.53 NC NC NC Mucus gland 1.89 2.29 1.93 0.031 BLOQ 2.02 6.92 d NC 23.0 Brown fat 1.30 1.88 1.36 BLOQ BLOQ 1.41 NC NC NC White fat 0.868 2.14 1.06 BLOQ BLOQ 0.884 NC NC NC Bulbo-urethral gland 1.17 1.42 1.08 b BLOQ BLOQ 1.27 NC NC NC Epididymis 0.773 0.851 0.715 BLOQ BLOQ 0.826 NC NC NC Preputial gland 1.87 2.61 2.30 0.076 BLOQ 2.04 6.15 d NC 27.9 Prostate 1.00 1.60 0.921 0.023 BLOQ 1.10 2.21 NC 13.2 Seminal vesicles 0.610 1.04 0.779 b BLOQ BLOQ 0.664 NC NC NC Testis 0.332 0.583 0.470 BLOQ BLOQ 0.356 NC NC NC Muscle 0.677 0.917 0.670 BLOQ BLOQ 0.721 NC NC NC Myocardium 1.38 1.83 1.15 BLOQ BLOQ 1.49 NC NC NC Tongue 1.05 1.25 1.04 0.012 BLOQ 1.13 2.65 d NC 12.2 Lens 0.062 0.134 0.214 0.037 BLOQ 0.076 3.58 NC 2.63 Uveal tract 0.477 0.727 0.504 0.016 BLOQ 0.504 3.49 d NC 6.74 Bone marrow 0.729 0.709 0.591 BLOQ BLOQ 0.804 NC NC NC Lung 1.35 1.65 1.04 BLOQ BLOQ 1.44 NC NC NC Nasal mucosa 0.911 0.601 0.532 0.283 0.175 1.13 29.3 NC 11.3 (22.1) Non-pigmented skin 0.653 1.04 1.44 0.018 BLOQ 0.706 3.94 d NC 13.0 Pancreas 1.86 2.42 1.56 BLOQ BLOQ 2.01 NC NC NC Peridontal membrane 0.638 0.571 0.920 BLOQ BLOQ 0.698 NC NC NC Spleen 1.89 b 1.86 b 1.23 0.024 BLOQ 2.07 2.28 NC 17.6 Tooth pulp 0.633 0.641 0.583 BLOQ BLOQ 0.680 NC NC NC Stomach mucosa 5.97 b 6.00 b 3.95 BLOQ BLOQ 5.83 NC NC NC Small intestine mucosa 1.91 b 3.27 b 3.43 0.197 BLOQ 2.01 20.7 NC 40.2 Caecum mucosa 1.02 3.32 b 2.40 b 0.202 BLOQ 1.11 16.3 d NC 32.6

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Large intestine mucosa 1.35 4.93 2.32 b 0.170 BLOQ 1.42 15.6 NC 37.1 Rectum mucosa 1.07 1.74 1.96 b 0.087 BLOQ 1.16 8.97 NC 21.8 HEC: Hydroxyethylcellulose BLOQ: Tissue radioactive concentration below lower limit of quantification. NC: Not calculated. ND: Radioactivity not detected. NS: Tissue not sectioned. a: For plasma and blood: radioactivity determined by liquid scintillation counting. b: Tissue measurement affected by “flaring” – measured concentration may be biased upwards. c: Determined in the range 0 – 24 h (in brackets: 0 – 72 h). d: Value only from 1 animal available (mean not calculated).

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表 2.6.5.5-3 Pharmacokinetics: Organ Distribution (Rat)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.3-2 Study No.: R20 318 ( 1010574) Species: Rat (Lister-Hooded pigmented) Gender (M/F)/Number of animals: M/1 per time point Feeding Condition: Fed Vehicle/Formulation: 0.5% HEC Method of Administration: p.o. Dose (mg/kg): 5 (calculated as free base) Radionuclide: 14C Specific Activity: 4.47 MBq/mg Analyte/Assay: [14C] Erlotinib / QWBA (autoradioluminography) Sampling Times: 1, 4, 8, 24, and 72 hours

Tissue concentration of radioactivity (μg equiv./g) (mean values) Tissue/plasma ratio

Tissues/Organs 1 h 4 h 8 h 24 h 72 h 1 h 24 h t1/2 (h) AUC c (μg equiv.•h/g)

Plasma a 1.10 0.808 0.415 0.009 ND 1.00 1.00 NC 7.44 Blood a 1.17 0.902 0.460 0.032 0.032 1.06 3.46 NC 8.87 (10.4) Blood 1.03 0.813 0.506 BLOQ BLOQ 0.934 NC NC NC Aorta 2.60 2.08 0.614 BLOQ BLOQ 2.36 NC NC NC Mandibular lymph nodes 1.25 1.11 NS BLOQ BLOQ 1.14 NC NC NC Kidney cortex 3.95 4.58 2.57 0.080 0.032 3.59 8.64 NC 40.2 (42.7) Kidney medulla 1.78 3.00 3.32 BLOQ BLOQ 1.62 NC NC NC Liver 5.44 5.79 3.70 0.267 0.096 4.95 28.9 NC 59.1 (67.2) Brain 0.146 0.094 0.061 BLOQ BLOQ 0.133 NC NC NC Choroid plexus 0.507 0.281 0.376 BLOQ BLOQ 0.461 NC NC NC Meninges 0.280 0.219 0.828 0.208 0.300 0.254 22.5 NC 10.2 (22.2) Pineal body 1.63 1.03 NS BLOQ BLOQ 1.48 NC NC NC Spinal cord 0.170 0.092 0.090 BLOQ BLOQ 0.154 NC NC NC Adrenal cortex 4.39 3.39 2.70 0.260 0.088 3.99 28.2 NC 42.6 (50.2) Adrenal medulla 2.32 NS 1.35 0.097 0.039 2.11 10.5 NC 21.3 (24.4) Pituitary 1.79 1.60 0.953 BLOQ BLOQ 1.63 NC NC NC

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Thymus 1.06 0.837 0.459 BLOQ BLOQ 0.962 NC NC NC Thyroid 1.89 1.67 NS 0.057 BLOQ 1.72 6.19 NC 15.8 Exorbital lachrymal gland 1.69 1.49 NS BLOQ BLOQ 1.54 NC NC NC Harderian gland 2.14 2.07 0.896 0.052 BLOQ 1.95 5.63 NC 17.7 Intra-orbital lachrymal gland 1.68 1.61 NS BLOQ BLOQ 1.53 NC NC NC Salivary glands 1.76 1.69 0.803 BLOQ BLOQ 1.60 NC NC NC Mucus gland 2.03 1.84 0.915 BLOQ BLOQ 1.85 NC NC NC Brown fat 2.29 1.91 1.116 BLOQ BLOQ 2.08 NC NC NC White fat 1.47 2.08 0.746 BLOQ BLOQ 1.33 NC NC NC Bulbo-urethral gland 1.82 NS 0.804 BLOQ BLOQ 1.65 NC NC NC Epididymis 0.940 0.770 0.781 BLOQ BLOQ 0.854 NC NC NC Preputial gland NS 2.25 1.82 0.051 BLOQ NC 5.56 NC 20.5 Prostate 1.27 1.21 0.781 BLOQ BLOQ 1.16 NC NC NC Seminal vesicles 0.611 0.792 0.518 BLOQ BLOQ 0.555 NC NC NC Testis 0.516 0.473 0.340 BLOQ BLOQ 0.469 NC NC NC Muscle 0.817 0.762 0.420 BLOQ BLOQ 0.743 NC NC NC Myocardium 1.61 1.45 0.760 BLOQ BLOQ 1.46 NC NC NC Tongue 1.30 1.10 0.577 BLOQ BLOQ 1.18 NC NC NC Lens 0.043 0.066 0.148 0.037 0.044 b 0.039 3.98 NC 1.89 (3.83) Uveal tract 21.8 36.2 37.3 11.8 8.87 19.8 1280 NC 599 (1090) Bone marrow 1.21 0.957 0.568 BLOQ BLOQ 1.10 NC NC NC Lung 1.60 0.943 0.671 BLOQ BLOQ 1.45 NC NC NC Nasal mucosa 0.401 0.347 0.481 0.367 0.154 0.364 39.7 NC 9.72 (21.5) Non-pigmented skin 0.791 0.905 0.360 BLOQ BLOQ 0.719 NC NC NC Pigmented skin 0.886 5.90 2.71 1.16 1.29 0.805 125 NC 56.3 (115) Pancreas 2.43 1.85 1.17 0.022 BLOQ 2.21 2.42 NC 18.2 Peridontal membrane 0.653 0.489 0.221 BLOQ BLOQ 0.594 NC NC NC Spleen 1.78 1.59 0.791 0.033 BLOQ 1.62 3.53 NC NC Tooth pulp 0.924 0.686 0.434 BLOQ BLOQ 0.840 NC NC NC Stomach mucosa 5.46 b 5.55 b 4.65 0.048 BLOQ 4.96 5.21 NC 55.7 Small intestine mucosa 27.2 b 6.95 b 4.14 0.346 BLOQ 24.7 37.42 NC 104 Caecum mucosa 2.48 2.29 b 6.07 b NS BLOQ 2.26 NC NC NC

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Large intestine mucosa 2.50 4.43 5.70 b 1.60 BLOQ 2.27 173 NC 83.5 Rectum mucosa 1.63 NS 0.447 b 0.076 0.024 1.48 8.25 NC 10.6 (12.7) HEC: Hydroxyethylcellulose BLOQ: Tissue radioactive concentration below lower limit of quantification. NC: Not calculated. ND: Radioactivity not detected. NS: Tissue not sectioned. a: For plasma and blood: radioactivity determined by liquid scintillation counting. b: Tissue measurement affected by “flaring” – measured concentration may be biased upwards. c: Determined in the range 0 – 24 h (in brackets: 0 – 72 h).

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2.6.5.6 薬物動態試験：たん白結合

表 2.6.5.6-1 Pharmacokinetics: Plasma Protein Binding

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.3-4 Study No.: I20 125 Study System: Mouse, Rat, Dog, and Human Plasma Concentration Range: 500 and 1000 ng/mL Duration of Experiment: Equilibrium dialysis, 20 hours with mixing (37°C) Assay: HPLC-UV

Species % Drug Protein Bound (Mean ± standard deviation [n=6]) Nu/nu Mouse 94.5 ± 0.49 Sprague-Dawley Rat 91.5 ± 3.17 Beagle Dog 85.1 ± 2.86 Human 91.6 ± 1.20

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表 2.6.5.6-2 Pharmacokinetics: Plasma Protein Binding

Test Article: OSI-420 (metabolite of erlotinib hydrochloride) Location in CTD: 4.2.2.3-5 Study No.: I 0015 ( DM -358774-08) Study System: Mouse, Rat, Dog, and Human Plasma Concentration Range: 500 and 1000 ng/mL Duration of Experiment: Equilibrium dialysis, 20 hours with mixing (37°C) Assay: HPLC-UV

Species: % Drug Protein Bound (Mean ± standard deviation [n=6]) CD-1 Mouse 73.0 ± 1.91 Sprague-Dawley Rat 77.5 ± 5.06 Beagle Dog 83.3 ± 1.19 Human 90.9 ± 1.40

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2.6.5.7 薬物動態試験：妊娠又は授乳動物における試験

表 2.6.5.7-1 Pharmacokinetics: Study in Pregnant or Nursing Animals (Placental Transfer)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.3-3 Study No.: ADM -0063 (B 0835) Species: Rat (BrlHan: WIST) Gender (M/F)/Number of animals: F/3 per time point Pregnancy: Day 19 Feeding Condition: Fed Vehicle/Formulation: 0.5% HEC Method of Administration: p.o. Dose (mg/kg): 5 (calculated as free base) Radionuclide: 14C Specific Activity: 4.77 MBq/mg Analyte/Assay: [14C] Erlotinib / Liquid scintillation counting Sampling Times: 1, 4, 8, and 24 hours

Tissue concentration of radioactivity (ng equiv./g) (mean values)

Tissue/plasma (dam) ratio (mean values)

Distribution of radioactivity (% of dose) (mean values)

Tissues/Organs 1 h 4 h 8 h 24 h 1 h 4 h 8 h 24 h 1 h 4 h 8 h 24 h Dam

Blood 1688.94 1421.55 1076.06 43.53 1.01 1.10 0.93 1.05 NC NC NC NC Plasma 1679.66 1288.68 1171.02 39.25 1.00 1.00 1.00 1.00 NC NC NC NC Cerebrum 341.57 248.15 258.41 7.34 0.20 0.20 0.22 0.21 0.032 0.023 0.025 0.001 Heart 2618.85 2152.97 1831.41 74.72 1.57 1.67 1.58 1.75 0.131 0.100 0.081 0.003 Lung 3034.53 2426.45 2108.42 86.25 1.82 1.88 1.81 2.19 0.191 0.166 0.133 0.006 Liver 9761.34 7932.85 6897.02 703.37 5.94 6.11 5.94 21.16 8.277 6.319 5.225 0.620 Kidney 5591.01 5205.98 4372.73 392.59 3.40 4.01 3.79 11.14 0.680 0.569 0.476 0.042 Mammary gland 4197.02 3671.27 3326.25 288.34 2.57 2.87 2.83 9.53 NC NC NC NC Ovary 3452.48 2757.18 2523.98 95.26 2.07 2.14 2.19 2.49 0.031 0.025 0.024 0.001 Uterus 1250.62 1145.00 1011.16 59.30 0.77 0.87 0.87 1.49 0.288 0.237 0.236 0.013 Placenta a 2098.24 1658.05 1374.23 85.73 1.25 1.29 1.17 2.36 0.063 0.051 0.037 0.003 Amniotic fluid a 338.42 603.30 655.46 156.05 0.22 0.46 0.55 4.58 NC NC NC NC Amnion a 1054.83 1074.85 879.74 226.73 0.63 0.82 0.76 6.15 NC NC NC NC

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表 2.6.5.7-1 Pharmacokinetics: Study in Pregnant or Nursing Animals (Placental Transfer) (続)

Tissue concentration of radioactivity (ng equiv./g) (mean values)

Tissue/plasma (dam) ratio (mean values)

Distribution of radioactivity (% of dose) (mean values)

Tissues/Organs 1 h 4 h 8 h 24 h 1 h 4 h 8 h 24 h 1 h 4 h 8 h 24 h

Fetus Whole-body a 859.22 713.69 806.46 524.75 0.51 0.56 0.71 18.13 0.158 0.156 0.198 0.187 Plasma b 1719.64 1187.84 1443.88 204.86 1.01 0.92 1.32 4.45 NC NC NC NC Brain a 354.42 228.03 221.89 8.19 0.21 0.17 0.19 0.20 0.004 0.003 0.003 0.000 Heart b 669.98 477.59 458.65 30.88 0.40 0.37 0.40 0.74 0.001 0.001 0.001 0.000 Lung a 698.35 498.16 544.75 35.30 0.41 0.38 0.47 0.82 0.005 0.005 0.005 0.001 Liver a 1175.10 857.15 866.78 128.71 0.70 0.66 0.75 3.29 0.021 0.018 0.021 0.004 Kidney b 896.65 694.67 644.23 60.70 0.53 0.54 0.56 1.48 0.001 0.001 0.001 0.000 GI tract a, c 1416.37 2986.88 5955.08 9254.51 0.91 2.37 5.28 237.08 0.013 0.036 0.093 0.156

NC: Not calculated. a: Individual result was obtained from two fetal tissues or bodies. b: Individual result was obtained from four to ten fetal tissues. c: Gastro-intestinal tract (including its content)

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表 2.6.5.7-2 Pharmacokinetics: Study in Pregnant or Nursing Animals (Excretion into Milk)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.5-2 Study No.: ADM -0064 (B 0836) Species: Rat (BrlHan: WIST) Gender (M/F)/Number of animals: F/3 Day after delivery: Day 13 Feeding Condition: Fed Vehicle/Formulation: 0.5% HEC Method of Administration: p.o. Dose (mg/kg): 5 (calculated as free base) Radionuclide: 14C Specific Activity: 4.77 MBq/mg Analyte/Assay: [14C] Erlotinib / Liquid scintillation counting Sampling Times: 0.5, 1, 2, 4, 8, 12, 24 and 48 hours

Sample (e.g., whole blood, plasma, serum): Milk Plasma Milk/Plasma Ratio PK Parameters of radioactivity:

tmax (h) 4.0 (0.0) 0.5 (0.0) N/A Cmax (ng equive./mL) 7593.60 (2013.99) 1364.43 (168.65) 5.53 (0.96) t1/2 (h) 5.4 (0.9) 3.9 (1.0) N/A AUC0-last (ng equive.•h/mL) 107456.2 (22408.0) 7443.9 (836.0) 14.65 (4.08) AUC0-inf (ng equive.•h/mL) 107794.1 (22116.5) 7573.9 (772.7) 14.40 (3.78)

Values represent the mean (standard deviation). N/A: Not applicable.

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2.6.5.8 薬物動態試験：その他の分布試験該当なし

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2.6.5.9 薬物動態試験：In vivo における代謝

表 2.6.5.9-1 Pharmacokinetics: In vivo Metabolism (Rat)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.4-7 Study No.: R 0021 Species: Sprague-Dawley Rat, Bile Canulated Gender (M/F)/No. of Animals: 2 M/2F bile cannulated for bile and urine, 2M/2F per time point for plasma Feeding Condition: Not Stated Vehicle/Formulation: 0.5% MC Method of Administration: p.o. Dose: 5 mg/kg (calculated as free base) Radionuclide: 14C Specific Activity: 17.39 mCi/mmol Biological Matrix: Urine, Bile, Plasma Sampling Time Period: See column headings for sampling time information Assays: LC-MS/MS coupled with simultaneous flow scintillation detection, liquid scintillation, and HPLC flow scintillation

% Radioactivity Urine Bile Plasma Male Female Male Female Male Male Male Female Female Female Metabolite: 0 – 48 h 0 – 48 h 0 – 24 h 0 – 24 h 1 h 4 h 8 h 1 h 4 h 8 h M1 (glucuronide of desmethyl-hydroxy erlotinib) 2.18 1.04 3.54 1.71 – – – – – – M2 (O-desmethyl OSI-493) 9.07 1.48 1.74 7.01 – – – – – – M3 (glucuronide of OSI-356) 0.82 7.59 6.81 0.59 – – – – – – M4 (sulfate of desmethyl-hydroxy erlotinib) 2.61 4.69 3.42 5.35 – – – – – – M5 (N-O-glucuronide of erlotinib) 7.08 4.65 8.24 5.35 – – – – – – M6 (OSI-493 [CP-457,493]) 19.89 38.67 27.22 38.96 3.30 – – 8.68 – – M7 (dihydro-dihydroxy erlotinib) 3.99 3.12 4.21 2.46 – – – – – – M8 (glucuronide of OSI-413) 2.86 4.35 3.78 3.66 – – – – – – M9 (sulfate of OSI-356) 6.65 5.71 2.12 6.22 – – – – – – M10 (glucuronide of OSI-420) 13.56 13.94 11.65 11.95 – – – – – –

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表 2.6.5.9-1 Pharmacokinetics: In vivo Metabolism (Rat) (続)

% Radioactivity Urine Bile Plasma Male Female Male Female Male Male Male Female Female Female Metabolite: 0 – 48 h 0 – 48 h 0 – 24 h 0 – 24 h 1 h 4 h 8 h 1 h 4 h 8 h M11 (carboxy-desmethyl erlotinib) 9.48 6.64 4.76 3.49 – – – – – – M12 (OSI-943 [CP-373,943]) 16.24 4.01 4.57 6.45 – – – – – – M13 (OSI-413 [CP-373,413]) 0.29 0.38 1.40 1.46 – 4.27 3.41 – 1.31 2.21 M14 (OSI-420 [CP-373,420]) 2.20 1.49 6.08 2.55 11.73 17.97 15.80 19.42 7.87 11.53 M15 (Erlotinib [CP-358,774]) 0.40 1.25 7.15 1.88 82.92 76.14 80.79 66.12 90.82 86.26 M16 (OSI-356 [CP-394,356]) – – – – 2.05 1.62 – 5.79 – – Column Total 97.29 98.97 96.64 99.05 100 100 100 100 100 100 –: Not detected. % total urinary excretion for 48 hours was 27.56 in males and 9.93 in females, % total biliary excretion for the same period was 52.65 in males and 67.35 in females.

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表 2.6.5.9-2 Pharmacokinetics: In vivo Metabolism (Rat)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.4-6 Study No.: R 0167 Study System: Sprague-Dawley Rat Gender (M/F)/No. of Animals: 3 M/3F Feeding condition: Fed Vehicle/Formulation: 0.5% MC Method of Administration: p.o. Dose: 5 mg/kg (calculated as free base) Radionuclide: 14C Specific Activity: 52.03 mCi/mmol Biological Matrix: Plasma Time points: 0.33, 0.67, 1, 2, 4, 8, 12, and 24 hours Assay: Liquid scintillation counting and LC-MS/MS

Cmax (ng/mL) t1/2 (h) AUC0-24h (ng•h/mL) Male Female Male Female Male Female Total Radioactivity 1044.5 826.6 4.99 3.41 4874.0 8606.4 Erlotinib 821.8 556.8 2.25 2.23 4294.2 6714.7

% of Total Radioactivity 78.7 67.4 N/A N/A 88.1 78.0 N/A: Not applicable.

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表 2.6.5.9-3 Pharmacokinetics: In vivo Metabolism (Dog)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.4-8 Study No.: D 0157 ( DM -358774-36) Species: Beagle Dog Gender (M/F)/No. of Animals: 2 M/2F Feeding Condition: Not Stated Vehicle/Formulation: 0.5% MC Method of Administration: p.o. Dose: 5 mg/kg (calculated as free base) Radionuclide: 14C Specific Activity: 49.0 mCi/mmol Biological Matrix: Urine, Feces Sampling Time Period: 0 to 144 hours Assays: Liquid scintillation counting, LC-MS/MS with flow scintillation detection, and HPLC with flow scintillation detection

Metabolite: % Radioactivity In Urine Samples (0 – 24 h)

% Radioactivity In Fecal Samples (0 – 48 h) % of Dosed Radioactivity In Urine and Fecal Samples

M2 (O-desmethyl OSI-493) 2.09 – 0.05 M3 (glucuronide of OSI-356) 7.21 – 0.18 M6 (OSI-493 [CP-457,493]) 20.72 7.28 7.66 M9 (sulfate of OSI-356) 6.23 – 0.16 M11 (carboxy-desmethyl erlotinib) 42.74 62.27 61.75 M12 (OSI-943 [CP-373,943]) 2.59 2.25 2.29 M13 (OSI-413 [CP-373,413]) – 0.67 0.66 M14 (OSI-420 [CP-373,420]) 0.45 8.56 8.40 M15 (erlotinib [CP-358,774]) 1.17 8.88 8.62 M16 (OSI-356 [CP-394,356]) 1.45 5.49 5.44 M17 (O-desmethyl OSI-356) 6.28 4.62 4.69 Column Total 90.93 100.01 99.91 –: Not detected. Overall, % total urinary excretion for 144 h both male and female dogs combined was 2.54 ± 0.21, % total combined fecal excretion for the same period was 97.6 ± 4.21. No gender-related differences in excretion were apparent.

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表 2.6.5.9-4 Pharmacokinetics: In vivo Metabolism (Dog)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.4-9 Study No.: D 0158 ( DM -358774-39) Species: Beagle Dog Gender (M/F)/No. of Animals: 2 M/2F Feeding Condition: Not Stated Vehicle/Formulation: 0.5% MC Method of Administration: p.o. Dose: 5 mg/kg (calculated as free base) Radionuclide: 14C Specific Activity: 49.0 mCi/mmol Biological Matrix: Plasma Time points: 0.33, 0.67, 1, 2, 4, 8, 12, 24, 48, and 72 hours Assays: Liquid scintillation counting and LC-MS/MS

Cmax (ng/mL) t1/2 (h) AUC0-24h (ng•h/mL) Male Female Male Female Male Female Total Radioactivity 1436.5 2125.8 4.02 2.45 4318.5 9755.3 Erlotinib 1048.9 1476.7 3.17 2.35 2889.7 7243.8

% of Total Radioactivity 70.1 67.6 N/A N/A 66.9 74.2 N/A: Not applicable.

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2.6.5.10 薬物動態試験：In vitro における代謝

表 2.6.5.10-1 Pharmacokinetics: In vitro Metabolism

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.4-1 Study No.: V 0014 Study System: Rat and Human Liver Microsomes Concentration Range: 10 μM Assay: LC-MS/MS and HPLC-UV

Metabolite: Rat Microsomes Human Microsomes Metabolite I (OSI-356 [CP-394,356], M16) Present Present Metabolite II (OSI-420 [CP-373,420], M14) Present Present Metabolite III (OSI-413 [CP-373,413], M13) Present Present Metabolite IV (OSI-943 [CP-373,943], M12) Present Present

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Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.4-3 Study No.: V 0015 Study System: Rat, Dog, and Human Liver Microsomes Concentration Range: 1 μM Timepoints of Experiment: 0, 5, 10, 15, 30, 45, and 60 minutes Assay: HPLC-UV

Metabolic half-life (minutes) Compound Rat Microsomes Dog Microsomes Human Microsomes CP-358,774-01 (OSI-774-01, Erlotinib)

>60 58 24

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Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.4-2 Study No.: V 0014 Study System: Rat and Human Liver Microsomes Radionuclide: 14C Substrate Concentration: 1 and 100 μM Sampling Time Period: 2 hours at 37°C Assays: LC-MS/MS and flow scintillation detection.

Rat Liver Microsomes a

Human Liver Microsomes

Rat Liver Microsomes a

Substrate Concentration 100 μM 100 μM 1 μM

Metabolite: M2 (O-desmethyl OSI-493) – – Present M6 (OSI-493 [CP-457,493]) Present Present Present M13 (OSI-413 [CP-373,413]) Present Present Present M14 (OSI-420 [CP-373,420]) Present Present Present M15 (Erlotinib [CP-358,774]) Present (~70%) Present (~70%) Consumed M16 (OSI-356 [CP-394,356]) Present Present Present M17 (O-desmethyl OSI-356) – – Present a: Phenobarbitol induced. –: Not detected.

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Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.4-4 Study No.: V 0013 ( DM -358774-10) Study System: Rat and Human Liver Microsomes, and Human Lymphoblast Microsome Concentration: 1 μM Timepoints of Experiment: 0, 5, 10, 15, 30, 45, and 60 minutes Assay: HPLC-UV

Species Lot No. CYP1A2 Activity (nmol/min/mg) P-450 Incubation Conc. (μM) Erlotinib t1/2 (min) Rat RL-111 0.6 a 0.5 >60 Rat RL BNF-2 b 11.4 a 0.5 <5 Human HL Mix-2 c 0.119 d 0.5 24 Human HL-1018 0.237 d 0.5 30 Human Gentest; 44 e 0.108 a 0.12 >60 a: Reaction monitored for CYP1A2 activity with ethoxy resorufin O-deethylation. b: Rats were administered an 80 mg/kg dose IP of the CYP1A inducer, β-napthaflavone, 3 days prior to sacrifice. c: HL Mix-2 Liver Microsomes contain CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 activity. d: Reaction monitored for CYP1A2 activity with phenacetin O-deethylation. e: Gentest; 44 Lymphoblast Microsomes express only CYP1A2 activity.

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Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.4-5 Study No.: V 0162 ( DM -358774-25) Study System: Rat Lung and Liver Microsomes, Human lymphoblast cell Concentrations: 1 μM (14C labeled plus unlabeled) Timepoints of Experiment: 0, 5, 10, 15, 20, and 30 minutes at 37°C Assay: HPLC-UV or flow scintillation detection

Species Lot No. CYP1A1 Activity c (nmol/min/mg)

P-450 Incubation Conc. (μM)

Erlotinib t1/2 (minutes)

Rat RL-BNF-2 a ND 0.50 <5 Rat RL-125 ND 0.50 >30 Rat RL-BNF-2 a, b ND 0.50 <5 Rat RL-125 b ND 0.50 >30 Rat Lung 0.07 0.05 >60 Rat Lung-BNF 0.16 0.10 37 Human Gentest d 0.45 0.10 15 ND: Not determined. a: Microsomes were treated with β-napthaflavone (BNF), a known inducer of CYP1A. b: Microsomes pre-incubated with the specific CYP1A2 inhibitor, Furafylline at 20 μM. c: Reaction monitored for CYP1A1 activity with ethoxy resorufin O-deethylation. d: Lymphoblast Microsomes express only CYP1A1 activity.

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Test Article: Erlotinib hydrochloride Location in CTD: 5.3.2.2-5 Study No.: V 0216 ( DM -358774-41) Study System: Human Liver Microsome, rhCYPs Concentrations: 0.5 – 100 μM (14C labeled) Timepoints of Experiment: 20 minutes at 37°C Assay: HPLC-radio chromatography

% inhibition of formation for each metabolite

Source of enzymes Inhibitors (target CYP) Inhibitor Conc. (μM) OSI-493 OSI-356 OSI-420/413

Human liver microsome Ketoconazole (3A4) 10 81.4 95.0 80.4 Human liver microsome Sulfaphenazole (2C9) 50 0.9 11.9 10.0 Human liver microsome Furafylline (1A2) 20 6.2 20.5 10.0 Human liver microsome Quinidine (2D6) 10 7.6 −4.3 −9.0 Human liver microsome ABT (non-specific) 5000 94.5 98.7 94.3 ABT: 1-aminobenzotriazole rhCYP3A4, 3A5, and 1A1 formed metabolites, OSI-493, OSI-356 and OSI-420/413. rhCYP1A2, 2D6, 2C9, and 2C19 formed no metabolite.

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2.6.5.11 薬物動態試験：推定代謝経路

N

NO

O

NH

OCH

3

OCH

3

CCH

N

NO

O

NH

OCH

3

OCH

3

CCH

OH

N

NO

O

NH

OCH3

OCH

3

OH

O

N

NO

O

NH

OCH

3

OH

CCH

OH

N

NO

O

NH

OCH

3

OH

OH

O

N

NO

O

NH

OCH3

OH

CCH

N

NO

O

NH

OH

OCH3

CCH

N

NO

O

NH

OH

OH

CCH

N

NO

O

NH

OH

OCH

3

CCH

O

N

NO

O

NH

OCH

3

OH

CCH

O

OSI-413 OSI-420

OSI-943

M11b M11a

OSI-356OSI-493

M2M17

Erlotinib

N

NO

O

NH

OCH

3

OCH

3

CCH

N

NO

O

NH

OCH

3

OCH

3

CCH

OH

N

NO

O

NH

OCH3

OCH

3

OH

O

N

NO

O

NH

OCH

3

OH

CCH

OH

N

NO

O

NH

OCH

3

OH

OH

O

N

NO

O

NH

OCH3

OH

CCH

N

NO

O

NH

OH

OCH3

CCH

N

NO

O

NH

OH

OH

CCH

N

NO

O

NH

OH

OCH

3

CCH

O

N

NO

O

NH

OCH

3

OH

CCH

O

OSI-413 OSI-420

OSI-943

M11b M11a

OSI-356OSI-493

M2M17

Erlotinib

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2.6.5.12 薬物動態試験：薬物代謝酵素の誘導／阻害

表 2.6.5.12-1 Pharmacokinetics: Induction/Inhibition of Drug-Metabolizing Enzymes (Inhibition of CYPs)

Test Article: Erlotinib hydrochloride, OSI-420 Location in CTD: 5.3.2.2-8 Study No.: V 0160 ( DM -358774-30) Study System: Human Liver Microsome (0.1 μM CYP or 0.1 – 0.5 mg/mL microsomal protein) Concentrations: 0 – 100 μM Incubation time: 20 – 30 minutes at 37°C Assay: HPLC-UV or HPLC-Fluorescence

Source of CYP CYP isoform Probe substrate Erlotinib IC50 (μM)

OSI-420 IC50 (μM)

Human liver microsome CYP1A2 Phenacetin (50 μM) >100 40 Human liver microsome CYP2C9 Diclofenac (10 μM) >100 >100 Human liver microsome CYP2C19 S-mephenytoin (50 μM) >100 >100 Human liver microsome CYP2D6 Bufuralol (10 μM) >100 70 Human liver microsome CYP3A4 Testosterone (20 – 50 μM) 18 23

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表 2.6.5.12-2 Pharmacokinetics: Induction/Inhibition of Drug-Metabolizing Enzymes (Inhibition of CYPs)

Test Article: Erlotinib hydrochloride, OSI-420 Location in CTD: 5.3.2.2-9 Study No.: V 0161 ( DM -358774-31) Study System: Human Liver Microsome (0.1 μM CYP or 0.5 mg/mL Microsomal protein) Concentrations: 0 – 80 μM for CYP1A2, 0 – 30 μM for CYP3A4 Incubation time: 20 minutes at 37°C Assay: HPLC-UV

Source of CYP CYP isoform Probe substrate Erlotinib Ki (μM) a

OSI-420 Ki (μM) a

Human liver microsome CYP1A2 Phenacetin (5 – 20 μM) ND 20 (1.0) Human liver microsome CYP3A4 Testosterone (10 – 160 μM) 8.0 (2.3) 24 (2.1) ND: Not determined; interaction had an IC50 value > 100 μM. a: Values represent the mean (standard deviation) of 3 samples.

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表 2.6.5.12-3 Pharmacokinetics: Induction/Inhibition of Drug-Metabolizing Enzymes (Inhibition of glucuronidation)

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.6-1 Study No.: V20 117 Study System: Human, rat and dog liver microsomes, expressed human UGT isozymes Concentrations: 0 – 250 μM Time points of Experiment: 30 – 60 minutes at 37°C (for bilirubin assay) Assay: UV 530 nm (for bilirubin assay)

Source of UGT Substrate Erlotinib concentration range (μM)

Erlotinib Ki (μM) a Competitive fit

Erlotinib Ki (μM) a Non competitive fit

Expressed human UGT1A1 bilirubin (15 – 122 μM) 0 – 4 0.7 (0.15) 1.5 (0.34) Human liver microsome bilirubin (15 – 122 μM) 0 – 4 1.3 (0.21) 4.6 (0.23) Rat liver microsome bilirubin (15 – 122 μM) 0 – 4 0.34 (0.11) 1.1 (0.28)


Erlotinib IC50 (μM)

Human UGT1A6 1-naphthol 0 – 250 No inhibition Human UGT1A9 Propofol 0 – 250 31 Human UGT2B7 hyodeoxycolic acid 0 – 250 No inhibition Human liver microsome 1-naphthol 0 – 250 No inhibition Human liver microsome propofol 0 – 250 24 Human liver microsome Hyodeoxycolic acid 0 – 250 No inhibition a: Mean value (standard deviation) Ki value was not determined in the dog liver microsome because of the low intrinsic bilirubin activity in the microsome.

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Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.6-2 Study No.: V20 131 Study System: Human, rat and dog liver microsomes, expressed human UGT1A1 Concentrations: 0 – 25 μM Time points of Experiment: 30 – 60 minutes at 37°C (for bilirubin assay) Assay: UV 530 nm (for bilirubin assay)



Human UGT1A1 bilirubin (122 μM) 0 – 25 0.93 Human UGT1A1 Octylgallate (500 μM) 0 – 25 0.17 Human liver microsome bilirubin (122 μM) 0 – 25 0.92 Rat liver microsome bilirubin (122 μM) 0 – 25 1.2 Dog liver microsome bilirubin (122 μM) 0 – 10 0.53

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Test Article: OSI-420 Location in CTD: 4.2.2.6-3 Study No.: V20 133 Study System: Human, dog, rat, and cynomolgus monkey liver microsomes, expressd human UGT 1A1 Concentrations: 0 – 125 μM Timepoints of Experiment: 30 – 60 minutes at 37°C Assay: UV 530 nm

Source of UGT Substrate OSI-420 concentration range (μM) OSI-420 IC50 (μM) UGT1A1 bilirubin (122 μM) 0 – 125 7.7 Human liver microsome bilirubin (122 μM) 0 – 125 8.7 Dog liver microsome bilirubin (122 μM) 0 – 125 6.8 Rat liver microsome bilirubin (122 μM) 0 – 125 8.3 Cynomolgus liver microsome bilirubin (122 μM) 0 – 125 7.9

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Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.6-4 Study No.: V20 134 Study System: Cynomolgus monkey liver microsome Concentrations: 0 – 25 μM Timepoints of Experiment: 30 – 60 minutes at 37°C Assay: UV 530 nm

Source of UGT Substrate Erlotinib Ki (μM) a Competitive fit

Erlotinib Ki (μM) a Non competitive fit

Cynomolgus monkey liver microsome

bilirubin (15 – 122 μM) 1.05 (0.22) 4.8 (1.3)



Cynomolgus monkey liver microsome

bilirubin (122 μM) 0 – 25 1.9

a: Mean value (standard deviation)

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表 2.6.5.12-7 Pharmacokinetics: Induction/Inhibition of Drug-Metabolizing Enzymes (Induction of CYP and transporter)

Test Article: Erlotinib hydrochloride Location in CTD: 5.3.2.2-10 Study No.: D 087 (1010720) Study System: LS-180 (Human intestinal cell line), primary human hepatocyte (fresh and cryopreserved) Concentrations: 1 – 100 μM for LS-180, 1 – 10 μM for hepatocyte Timepoints of Experiment: 72 h incubation for LS-180, 48 h incubation for hepatocyte Assay: Quantitative RT-PCR, LC-MS/MS, Western immunoblotting

LS-180 CYP3A4 mRNA a MDR-1 mRNA a Erlotinib 1 μM 1.82 (0.30) 1.24 (0.05) 10 μM 3.99 (0.13) 1.91 (0.12) 100 μM 13.01 (1.45) 3.49 (0.30) Rifampicin 1 μM 5.88 (0.85) 5.17 (0.68) 10 μM 9.00 (1.42) 5.42 (0.63) 100 μM 2.82 (0.32) b 4.86 (0.23) b a: Mean levels relative to vehicle-treated control (standard error). b: Decreased may be due to toxicity at 100 μM concentration of Rifampicin.

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表 2.6.5.12-7 Pharmacokinetics: Induction/Inhibition of Drug-Metabolizing Enzymes (Induction of CYP and transporter) (続)

Primary Human hepatocyte CYP2C9 mRNA c

CYP3A4 mRNA c

CYP3A4 Enzyme activity c

CYP1A2 mRNA d

MDR-1 mRNA c

MRP2 mRNA c

Erlotinib 1 μM 1.03 – 1.87 1.27 – 20.14 0.87 – 4.26 4.07 0.73 – 0.96 0.82 – 1.12 3.2 μM 1.00 – 2.67 4.07 – 44.52 0.87 – 2.16 5.32 0.75 – 1.06 1.02 – 1.25 10 μM 1.38 – 3.81 10.15 – 116.90 1.03 – 3.46 6.48 0.69 – 1.29 1.35 – 2.03 Rifampicin 1 μM 1.28 – 2.09 15.33 – 43.90 2.07 – 8.86 0.97 1.24 – 2.55 1.25 – 1.66 3.2 μM 0.99 – 3.53 30.80 – 105.31 3.18 – 10.28 1.07 1.62 – 2.28 1.03 – 1.99 10 μM 1.34 – 2.82 31.57 – 122.07 3.60 – 10.29 0.81 1.47 – 2.24 1.36 – 2.24 c: Range indicates fold induction observed from four human hepatocyte donors. d: Detected from one donor.

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2.6.5.13 薬物動態試験：累積排泄

表 2.6.5.13-1 Pharmacokinetics: Excretion

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.5-1 Study No.: R20 312 (1008502) Species: Wistar Rat Gender (M/F)/No. of Animals: 5 M per group Feeding Condition: Not Stated Vehicle/Formulation: 0.5% HEC for p.o., 50% PEG400 for i.v. Method of Administration: p.o., i.v. Dose: 5.19 mg/kg for p.o., 2.20 mg/kg for i.v. Radionuclide: 14C Specific Activity: 15 μCi/mg for p.o., 30 μCi/mg for i.v. Sampling Time Period: 0 – 96 h Assays: Liquid scintillation counting

Radioactivity (% of dose) a 0 – 24 h 24 – 48 h 48 – 72 h 72 – 96 h 0 – 96 h After p.o. administration Urine 3.42 (0.32) 0.20 (0.05) 0.05 (0.01) 0.03 (0.00) 3.70 (0.33) Feces 76.14 (4.42) 15.40 (3.73) 1.12 (0.25) 0.19 (0.05) 92.85 (1.91)Cages wash NS NS NS NS 0.12 (0.02) Recovery total NC NC NC NC 96.68 (1.02) After i.v. administration Urine 5.52 (0.93) 0.20 (0.09) 0.06 (0.02) 0.05 (0.03) 5.83 (1.00) Feces 71.65 (13.05) 15.92 (9.88) 2.50 (3.36) 0.33 (0.21) 90.40 (1.36)Cages wash NS NS NS NS 0.22 (0.11) Recovery total NC NC NC NC 96.45 (1.79) 0.5% HEC: 0.5% Hydroxyethylcellulose, 0.1% Polysorbat 80, 0.09% Nipagin and 0.01% Nipasol. NS: No sample NC: Not calculated a: Mean value (standard deviation)

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表 2.6.5.13-2 Pharmacokinetics: Excretion

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.4-8 Study No.: D 0157 ( DM -358774-36) Species: Beagle dog Gender (M/F)/No. of Animals: 2 M/2F Feeding Condition: Not Stated Vehicle/Formulation: 0.5% MC Method of Administration: p.o. Dose: 5 mg/kg (calculated as free base) Radionuclide: 14C Specific Activity: 49.0 mCi/mmole Sampling Time Period: 0 – 144 h Assays: Liquid scintillation counting

Radioactivity (% of dose) a 0 – 48 h 0 – 144 h Urine 2.27 (0.24) 2.54 (0.21) Feces 92.55 (6.32) 97.60 (4.21) Recovery total 94.82 (6.42) 100.13 (4.37) a: Mean value (standard deviation) No gender-related differences in excretion were apparent.

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2.6.5.14 薬物動態試験：胆汁中排泄

表 2.6.5.14-1 Pharmacokinetics: Excretion into Bile

Test Article: Erlotinib hydrochloride Location in CTD: 4.2.2.4-7 Study No.: R 0021 Species: Sprague-Dawley Rat, Bile Canulated Gender (M/F)/No. of Animals: 2 M/2F Feeding Condition: Not Stated Vehicle/Formulation: 0.5% MC Method of Administration: p.o. Dose: 5 mg/kg (calculated as free base) Radionuclide: 14C Specific Activity: 17.39 mCi/mmole Sampling Time Period: 0 – 48 h Assays: Liquid scintillation counting

0 - 48 h Radioactivity (% of dose) a Male Female Overall Urine 27.56 9.93 18.74 Bile 52.65 67.35 60.00 Recovery total 80.20 77.28 78.74 a: Mean value

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2.6.5.15 薬物動態試験：薬物相互作用該当なし

2.6.5.16 薬物動態試験：その他該当なし

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