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The New ICH Guideline on Genotoxicity (S2)

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(1)

ICH S2の概要および遺伝毒性研究に

おける発がん性の意味

本間 正充

(2)

TOPICS

 ICH S2(R1)ガイドライン のポイント

 他のガイドラインや研究分野への影響

 遺伝毒性発がん物質のリスク評価と管理

(案)

(3)

The International Conference on Harmonisation

of Technical Requirements for the Registration of

Pharmaceuticals for Human Use (ICH)

The ICH is an initiative undertaken by three regions, the European Union, Japan and the United States, with six co-sponsors

• European Union (EU)

• US Food and Drug Administration (FDA)

• Japanese Ministry of Health, Labour and Welfare (MHLW)

• European Federation of Pharmaceutical Industries and Associations (EFPIA) • Japan Pharmaceutical Manufacturers Association (JPMA)

(4)

Q

"Quality" Topics

, i.e., those relating to chemical and pharmaceutical Quality

Assurance.

Examples: Q1 Stability Testing, Q3 Impurity Testing

S

"Safety" Topics

, i.e., those relating to in vitro and in vivo pre-clinical studies.

Examples: S1 Carcinogenicity Testing, S2 Genotoxicity Testing

E

"Efficacy" Topics

, i.e., those relating to clinical studies in human subject.

Examples: E4 Dose Response Studies, Carcinogenicity Testing, E6 Good

Clinical Practices. (Note Clinical Safety Data Management is also classified as

an "Efficacy" topic - E2)

M

"

Multidisciplinary" Topics

, i.e., cross-cutting Topics which do not fit uniquely

into one of the above categories.

(5)

ICH Guideline of S2A and S2B

(http://www.ich.org/cache/compo/276-254-1.html)

(6)

Standard Battery of Genotoxicity Tests in ICH

(1997)

Bacterial Reverse Mutation Assay

Chromosome Aberration Test

or

Mouse Lymphoma Assay (MLA)

Micronuclei Test

In Vitro; 2 Tests

In Vivo; 1 test

(7)

Ames

58.8

73.9

54.0

79.0

MLA

73.1

39.0

74.0

32.0

Chrom.

Ab.

65.6

44.9

52.0

68.0

MN

(Vitro)

78.7

30.8

MN

(Vivo)

28.0

82.0

Sens.

Spec.

Sens

.

Spec.

Krikland et al.,

Mutat. Res. 584, 1,

2005

Zeiger

Reg. Tox. Pharm. 28,

85, 1998

Reports

Sens. (Sensitivity): % of positive results among rodent carcinogens.

Spec. (Specificity): % of negative results among rodent non-carcinogens.

Performance of Individual Genotoxicity Tests in

Detecting Rodent Carcinogens

(8)

High Frequency of Positive Results of in Vitro

Mammalian Cell Genotoxicity Test

The positive results are generally week and not relevant under in

vivo condition.

The positive results are due to un-physiological experimental

conditions (high cytotoxicity, insolubility), but not to true

genotoxicity.

The positive results lead to a great deal of follow-up testing (in vivo)

to assess whether there is any genotoxic risk.

We should take actions to reduce the high frequency of in vitro test and

avoid the wasteful follow-up tests.

(9)

Process of Revision of the S2 Guideline in ICH

June 2006 in Yokohama, Japan October 2006 in Chicago, USA May 2007 In Brussels, Belgium October 2007 In Yokohama, Japan February 2008 June 2008 In Portland, USA May 2009 In Yokohama, Japan

The ICH Steering Committee (SC) agreed to initiate a revision of the genotoxicity guideline (Step 1).

The ICH Expert Working Group (EWG) discuss revision and plan the approach to a revised guideline.

The EWG reached a consensus of the revised issues and agree to make a draft guideline according to the consensus.

The EWG finalized the new guideline for Step2.

Postal sign-off for Step2.

The EWG worked for answering public comments and further discussed for Step 4.

The step 4 process ?

(10)

The EWG will not sign off on

the Step 4 in Yokohama .

(11)
(12)
(13)

Major Revisions in S2 (R1)

 Mammalian cell assays:

 Decreased top dose from 10 mM to 1 mM

 Reinforce cytotoxicity limits

 Two options considered equally acceptable:

 Option 1: Battery with in vitro mammalian cell assay

 Ames

 In vitro mammalian cell assay

 In vivo micronucleus test (integrated into repeat-dose

toxicology study if possible)

 Option 2: Battery without in vitro mammalian cell assay

 Ames

 Genotoxicity measured in vivo in two different tissues,

(integration or combination if possible)

(14)

Proposed New Recommended Test Battery

Ames

In vitro mammalian cell test

Positive

Negative

MNT

(integrated if

possible)

(No 2nd in vivo)

Option 1

Option 2

a

b

No in vitro mammalian cell test

MNT

(integrated if possible)

+

2nd end-point/tissue

MNT

(integrated if possible)

+

2nd end-point/tissue

(integrated or combined

if possible)

(15)

Choice of In Vivo Assays: 2nd Endpoint / Tissue

 Liver typically preferred tissue, but choice should

be based on factors such as

 type of effect seen in vitro

 any knowledge of the potential mechanism

 of the exposed tissues thought to be relevant

 Options considered as acceptable

 DNA strand break assays (Comet, alkaline elution)

 Transgenic animal mutation assays

 UDS assay

Comet assay in liver is highly recommended

as the 2

nd

in vivo test

(16)

Impacts on Other International Guidelines

 OECD:

 Development of new in vivo genotoxicity test

guidelines

 Transgenic Rodent Somatic and Germ Cell Gene Mutation

Assays (TG488, July 2011)

 In vivo Comet assay (under validation)

 Revision of in vitro mammalian cell assays

 Reduction of top dose (from 10mM to ?)

 Deletion, refinement, and development of TGs (MLA)

 ICH-M7:

Development of DNA reactive (mutagenicity)

impurity guideline

(17)

HAZARD VERSUS RISK

Paradigm Shift in Genetic Toxicology;

From Hazard Identification to Risk Assessment

 Hazard Identification (Weight of Evidence)

 Hazard Characterization (Mode of Action)

 Exposure Assessment

(18)

遺伝毒性 VS 発がん物質

遺伝毒性・発がん物質

遺伝毒性・非発がん物質

非遺伝毒性・発がん物質

非遺伝毒性・非発がん物質

遺伝毒性陽性結 果は無視される 遺伝毒性陰性結 果は無視される

遺伝毒性偽陽性?

エピジェネティック?

(19)

直接遺伝毒性

発がん物質

間接遺伝毒性

発がん物質

非遺伝毒性

発がん物質

遺伝毒性からみた発がん物質の特徴

•DNAへ直接作用

•DNA損傷あり

•突然変異の誘発あり

•閾値なし

•不可逆的変化

•DNAへ間接作用

•DNA損傷なし

•突然変異の誘発あり

•閾値あり

•不可逆的変化

•DNAへ間接作用

•DNA損傷なし

•突然変異の誘発なし

•閾値あり

•可逆的変化

放射線 紫外線 アルキル化剤 多環芳香族炭化水素 芳香族アミン アフラトキシン 塩素化合物 ペルオキシゾーム増殖剤 ホルボールエステル ホルモン類 催眠薬(フェノバルビタール) DNA合成阻害剤 トポイソメラーゼ阻害剤 細胞分裂阻害剤

(20)

遺伝毒性閾値とTTC

用量

反応

用量

反応

閾値あり化合物

(非遺伝毒性物質・

間接遺伝毒性物質)

閾値なし化合物

(直接遺伝毒性物質)

閾値 閾値なし 安全性量

用量

安全性量?

反応

閾値を問わない

実質安全性量(VSD)

TTC

(21)

1.5μg/person/day

未知の化学物質の10%が発がん物質と仮定して、その99%が10

-5

発がんリスクで担保される設定閾値

食事中に低レベルで存在する

非遺伝毒性発がん物質

医薬品中に不純として含まれる

遺伝毒性(変異原性)発がん物質

TTC

レベル

0.15μg/person/day

未知の化学物質の10%が発がん物質と仮定して、その99%が10

-6

発がんリスクで担保される設定閾値

食事中に低レベルで存在する

遺伝毒性(変異原性)発がん物質

(22)

医薬品の不純物に関するICHガイドライン

ICH Q3B: 製剤の不純物に関するガイドライン

最大一日投与量

安全性確認が必要な閾値

<10 mg

1.0%

又は 5 0 μg/日の低い方

10 mg

~ 100mg

0.5%

又は200 μg /日の低い方

100 mg

~ 2 g

0.2%

又は3 mg/日の低い方

>2 g

0.15%

Marketed Product

Duration of

Treatment

≤1 month

1-12

months

1-10 years

> 10 years

Daily Intake

(µg/day)

120

20

10

1.5

3mg/日まで許容

(23)

遺伝毒性発がん性物質

適切なリスク評価

適切なリスク管理

発がん性を考慮した定量的評価

個別評価

(24)

Risk mitigation

Cohort of concern

発がん性 vs 遺伝毒性(エームス試験)

• メカニズム解析

• 化学構造クラス分類

• 他の試験によるフォローアップ

• 新しい試験法の開発

鈴木孝昌 Environ. Mutagen Res., 24:179-184(2002)

(25)

発がん性 vs 遺伝毒性(TG試験)

• 遺伝毒性試験結果の定量化

• 発がん性との量的相関性

鈴木孝昌 Environ. Mutagen Res., 24:179-184(2002)

(26)

まとめ

遺伝毒性発がん性物質のリスク評価と管理

ーハザードからリスクへー

適切な条件下でのin vitro試験の実施

メカニズムに基づくin vivo/in vitro試験法の開発

包括的リスク管理(TTC)と、個別のリスク管理

適切なリスク評価のための手法の開発

遺伝毒性試験結果の定量化と、発がん性リスク評価へ

参照

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