m4 safety step 4 sept02

8/12/2019 M4 Safety Step 4 Sept02

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INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICALREQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE

ICH HARMONISEDTRIPARTITEGUIDELINE

THECOMMONTECHNICALDOCUMENTFORTHEREGISTRATIONOFPHARMACEUTICALSFORHUMANUSE:

SAFETY M4S

NONCLINICALOVERVIEWANDNONCLINICALSUMMARIESOFMODULE2

ORGANISATIONOFMODULE4

Having reached Step 4 of the ICH Process at the ICH Steering Committeemeeting

on 9 November 2000, this guideline is recomm ended foradoption to the three regulatory parties to ICH

(Numbering and Section Headers have been edited for consistency and use in e-

CTD d t th W hi t DC M ti S t b 11 12 2002)


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CTD as agreed at the Washington DC Meeting September 11 12 2002)

The Common Technical Document - Safety

THECOMMONTECHNICALDOCUMENTFORTHEREGISTRATIONOFPHARMACEUTICALSFORHUMANUSE:

SAFETY

NONCLINICALOVERVIEWANDNONCLINICALSUMMARIESOFMODULE2

ORGANISATIONOFMODULE4

ICH Harmonised Tripartite Guideline

Having reachedStep 4

of the ICH Process at the ICH Steering Committeemeeting

on 9 November 2000, this guideline is recomm ended for

adoption to the three regulatory parties to ICH(Numbering and Section Headers have been edited for consistency and use in e-

CTD as agreed at the Washington DC Meeting, September 11-12, 2002)

TABLE OF CONTENTS

(This document includes the typographic correction on page 46 : to readpoint 2.6.7.3, agreed by the Steering Committee on 20December 2002) . ...................................................................................i

Module 2 : Common Technical Document Summaries ....................................1

General Principles of Nonclinical Overview and Summaries .....................................1


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2.6.4.1 Brief Summary .......................................................................................... 7

2.6.4.2 Methods of Analysis..................................................................................7

2.6.4.3 Absorption ..................................................................................................7

2.6.4.4 Distribution................................................................................................7

2.6.4.5 Metabolism (interspecies comparison) .................................................7

2.6.4.6 Excretion ....................................................................................................7

2.6.4.7 Pharmacokinetic Drug Interactions .......................................................7

2.6.4.8 Other Pharmacokinetic Studies ..............................................................8

2.6.4.9 Discussion and Conclusions ....................................................................8

2.6.4.10 Tables and Figures.................................................................................8

2.6.5 Pharmacokinetics Tabulated Summary (see Appendix B)...............................8

2.6.6 Toxicology Written Summary ...............................................................................8

2.6.6.1 Brief Summary .......................................................................................... 8

2.6.6.2 Single-Dose Toxicity .................................................................................9

2.6.6.3 Repeat-Dose Toxicity (including supportive toxicokineticsevaluation).............................................................................................9

2.6.6.4 Genotoxicity ...............................................................................................9

2.6.6.5 Carcinogenicity (including supportive toxicokinetics evaluations) . .9

2 6 6 6 R d ti d D l t l T i it (i l di g g fi di g


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MODULE2 : COMMONTECHNICALDOCUMENTSUMMARIES

General Principles of Nonclinical Overview and Summaries

This guideline provides recommendations for the harmonisation of the NonclinicalOverview, Nonclinical Written Summary, and Nonclinical Tabulated Summaries.

The primary purpose of the Nonclinical Written and Tabulated Summaries should be toprovide a comprehensive factual synopsis of the nonclinical data. The interpretation ofthe data, the clinical relevance of the findings, cross- linking with the quality aspects ofthe pharmaceutical, and the implications of the nonclinical findings for the safe use of

the pharmaceutical (i.e., as applicable to labeling) should be addressed in theOverview.

2.4 NONCLINICAL OVERVIEW

The Nonclinical Overview should provide an integrated overall analysis of theinformation in the Common Technical Document. In general, the Nonclinical Overviewshould not exceed about 30 pages.

General AspectsThe Nonclinical Overview should present an integrated and critical assessment of thepharmacologic, pharmacokinetic, and toxicologic evaluation of the pharmaceutical.Where relevant guidelines on the conduct of studies exist, these should be taken intoconsideration, and any deviation from these guidelines should be discussed and

justified. The nonclinical testing strategy should be discussed and justified. Thereshould be comment on the GLP status of the studies submitted. Any associationbetween nonclinical findings and the quality characteristics of the human

h ti l th lt f li i l t i l ff t ith l t d d t


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Content and Structural Format

The Nonclinical Overview should be presented in the following sequence :

Overview of the nonclinical testing strategyPharmacology

Pharmacokinetics

Toxicology

Integrated overview and conclusions

List of literature references

Studies conducted to establish the pharmacodynamic effects, the mode of action, and

potential side effects should be evaluated and consideration should be given to thesignificance of any issues that arise.

The assessment of the pharmacokinetic, toxicokinetic, and metabolism data shouldaddress the relevance of the analytical methods used, the pharmacokinetic models,and the derived parameters. It might be appropriate to cross-refer to more detailedconsideration of certain issues within the pharmacology or toxicology studies (e.g.impact of the disease states, changes in physiology, anti-product antibodies, cross-species consideration of toxicokinetic data). Inconsistencies in the data should be

discussed. Inter-species comparisons of metabolism and systemic exposurecomparisons in animals and humans (AUC, Cmax, and other appropriate parameters)should be discussed and the limitations and utility of the nonclinical studies forprediction of potential adverse effects in humans highlighted.

The onset, severity, and duration of the toxic effects, their dose-dependency anddegree of reversibility (or irreversibility), and species- or gender-related differencesshould be evaluated and important features discussed, particularly with regard to:

h d i


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The evaluation of toxicology studies should be arranged in a logical order so that allrelevant data elucidating a certain effect / phenomenon are brought together.Extrapolation of the data from animals to humans should be considered in relation to:

animal species used

numbers of animals used

routes of administration employed

dosages used

duration of treatment or of the study

systemic exposures in the toxicology species at no observed adverse effectlevels and at toxic doses, in relation to the exposures in humans at themaximum recommended human dose. Tables or figures summarising thisinformation are recommended.

the effect of the drug substance observed in nonclinical studies in relation to

that expected or observed in humans

If alternatives to whole-animal experiments are employed, their scientific validityshould be discussed.

The Integrated Overview and Conclusions should clearly define the characteristics ofthe human pharmaceutical as demonstrated by the nonclinical studies and arrive atlogical, well-argued conclusions supporting the safety of the product for the intendedclinical use. Taking the pharmacology, pharmacokinetics, and toxicology results intoaccount, the implications of the nonclinical findings for the safe human use of thepharmaceutical should be discussed (i.e., as applicable to labeling).

2.6 NONCLINICAL WRITTEN AND TABULATED SUMMARIES


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General Presentation Issues

Order of Presentation of Information within Sections

When available, in vitro studies should precede in vivo studies.

Where multiple studies of the same type need to be summarised within thePharmacokinetics and Toxicology sections, studies should be ordered by species, byroute, and then by duration (shortest duration first).

Species should be ordered as follows:

Mouse

Rat

Hamster

Other rodent

Rabbit

Dog

Non-human primate

Other non-rodent mammal

Non-mammals

Routes of administration should be ordered as follows :

The intended route for human use

Oral

Intravenous


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Length of Nonclinical Written Summaries

Although there is no formal limit to the length of the Nonclinical Written Summaries, itis recommend ed that the total length of the three Nonclinical Written Summaries ingeneral not exceed 100-150 pages.

Sequence of Written Summaries and Tabulated Summaries

The following order is recommended:

Introduction

Written Summary of Pharmacology

Tabulated Summary of Pharmacology

Written Summary of Pharmacokinetics

Tabulated Summary of Pharmacokinetcs

Written Summary of Toxicology

Tabulated Summary of Toxicology

Content of Nonclinical Written and Tabulated Summaries

2.6 .1 Introduction

The aim of this section should be to introduce the reviewer to the pharmaceutical andto its proposed clinical use. The following key elements should be covered:

Brief information concerning the pharmaceuticals structure (preferably, a

structure diagram should be provided) and pharmacologic properties.

I f ti i th h ti l d li i l i di ti d


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2.6.2.2 Primary Pharmacodynamics

Studies on primary pharmacodynamics* should be summarised and evaluated. Wherepossible, it would be helpful to relate the pharmacology of the drug to available data

(in terms of selectivity, safety, potency, etc.) on other drugs in the class.

2.6.2.3 Secondary Pharmacodynamics

Studies on secondary pharmacodynamics* should be summarised by organ system,where appropriate, and *evaluated in this section.

2.6.2.4 Safety Pharmacology

Safety pharmacology studies* should be summarised and evaluated in this section. In

some cases, secondary pharmacodynamic studies can contribute to the safetyevaluation when they predict or assess potential adverse effect(s) in humans. In suchcases, these secondary pharmacodynamic studies should be considered along withsafety pharmacology studies.

2.6.2.5 Pharmacodynamic Drug Interactions

If they have been performed, pharmacodynamic drug interaction studies should bebriefly summarised in this section.

2.6.2.6 Discussion and Conclusions

This section provides an opportunity to discuss the pharmacologic evaluation and toconsider the significance of any issues that arise.

2.6.2.7 Tables and Figures

Text tables and figures can be included at appropriate points throughout the summarywithin the text. Alternatively, tables and figures can be included at the end of the


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2.6.4.1 Brief Summary

The principal findings from the pharmacokinetics studies should be briefly summarizedin approximately 2 to 3 pages. This section should begin with a description of the

scope of the pharmacokinetic evaluation, emphasising, for example, whether thespecies and strains examined were those used in the pharmacology and toxicologyevaluations, and whether the formulations used were similar or identical.

2.6.4.2 Methods of Analysis

This section should contain a brief summary of the methods of analysis for biologicalsamples, including the detection and quantification limits of an analytical procedure. Ifpossible, validation data for the analytical method and stability of biological samples

should be discussed in this section. The potential impact of different methods ofanalysis on the interpretation of the results should be discussed in the followingrelevant sections.

2.6.4.3 Absorption

The following data should be summarised in this section:

Absorption (extent and rate of absorption, in vivo and in situ studies)

Kinetic parameters, bioequivalence and/or bioavailability (serum/plasma/blood

PK studies)

2.6.4.4 Distribution

The following data should be summarised in this section:

Tissue distribution studies

Protein binding and distribution in blood cells

Pl t l t f t di


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2.6.4.8 Other Pharmacokinetic Studies

If studies have been performed in nonclinical models of disease (e.g., renally impairedanimals), they should be summarised in this section.

2.6.4.9 Discussion and Conclusions

This section provides an opportunity to discuss the pharmacokinetic evaluation and toconsider the significance of any issues that arise.

2.6.4.10 Tables and Figures

Text tables and figures can be included at appropriate points throughout the summarywithin the text. Alternatively, there is the option of including tables and figures at the

end of the summary.

2.6.5 Pharmacokinetics Tabulated Summary (see Appendix B)

2.6.6 Toxicology Written Summary

The sequence of the Toxicology Written Summary should be as follows:

Brief Summary

Single-Dose Toxicity

Repeat-Dose Toxicity

Genotoxicity

Carcinogenicity

Reproductive and Developmental Toxicity

Studies in Juvenile Animals


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TOXICOLOGY PROGRAMME

Study type andduration

Route ofadministration

Species Compoundadministered*

Single-dosetoxicitySingle-dosetoxicityRepeat-dosetoxicity

1 month

6 months9 months,etc.

po and ivpo and iv

popopo

Rat and mouseRat and mouse

Rat and dogRatDog

Parent drugMetabolite X

Parent drug

* This column required only if metabolite(s) are investigated.

The scope of the toxicologic evaluation should be described in relation to the proposedclinical use. A comment on the GLP status of the studies should be included.

2.6.6.2 Single- Dose Toxicity

The single-dose data should be very briefly summarised, in order by species, by route.In some instances, it may be helpful to provide the data in the form of a table.

2.6.6.3 Repeat- Dose Toxicity (including supportive toxicokinetics evaluation)

Studies should be summarised in order by species, by route, and by duration, givingbrief details of the methodology and highlighting important findings (e.g., nature and

it f t t t i it d ( )/ l ti hi b d


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Other studies

2.6.6.6 Reproductiv e and Developmental Toxicity (including rangefinding studies andsupportive toxicokinetics evaluations)

Studies should be summarised in the following order, giving brief details of themethodology and highlighting important findings:

Fertility and early embryonic development

Embryo-fetal development

Prenatal and postnatal development, including maternal function

Studies in which the offspring (juvenile animals) are dosed and/or furtherevaluated, if such studies have been conducted.

If modified study designs are used, the sub-headings should be modified accordingly.

2.6.6.7 Local Tolerance

If local tolerance studies have been performed, they should be summarised in order byspecies, by route, and by duration, giving brief details of the methodology andhighlighting important findings.

2.6.6.8 Other Toxicity Studies (if available)

If other studies have been performed, they should be summarised. When appropriate,the rationale for conducting the studies should be provided.

Antigenicity

Immunotoxicity

Mechanistic studies (if not reported elsewhere)


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can modify the format if needed to provide the best possible presentation of theinformation and to facilitate the understanding and evaluation of the results.

This Guideline is not intended to indicate what studies are requested, but solely to

advise how to tabulate study results if a study is performed. Applicants might need toadd some items to or delete some items from the cited format where appropriate. Onetabular format can contain results from several studies. Alternatively, it may beappropriate to cite the data resulting from one study in several tabular formats.

The recommende d formats for the tables in the Nonclinical Tabulated Summaries areprovided in Appendices B and C, which follow. Appendix B contains templates for usein preparation of the tables. The templates are annotated (in italics) to provideguidance on their preparation. (The italicized information should be deleted when the

tables are prepared.) Appendix C provides examples of the summary tables. Thepurpose of the examples is to provide additional guidance on the suggested contentand format of the Tabulated Summaries. However, it is the responsibility of theapplicant to decide on the best possible presentation of the data for each product.

Authors should keep in mind that, in some regions, a review of the TabulatedSummaries (in conjunction with the Written Summaries) represents the primary reviewof the nonclinical information. Presentation of the data in the formats provided astemplates and examples should ensure that a sufficient level of detail is available to

the reviewer and should provide concise overviews of related information.When a juvenile-animal study has been conducted, it should be tabulated using thetemplate appropriate for the type of study.

The order of presentation given for the Nonclinical Written Summaries should befollowed for the preparation of the tables for the Nonclinical Tabulated Summaries.


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MODULE4: NONCLINICALSTUDYREPORTSThis guideline presents an agreed format for the organisation of the nonclinical reportsin the Common Technical Document for applications that will be submitted toRegulatory Authorities. This guideline is not intended to indicate what studies arerequired. It merely indicates an appropriate format for the nonclinical data that havebeen acquired.

The appropriate location for individual-animal data is in the study report or as anappendix to the study report.

4.1 Table of Contents of Module 4

A Table of Contents should be provided that lists all of the nonclinical study reportsand gives the location of each study report in the Common Technical Document.

4.2 Study Reports

The study reports should be presented in the following order:

4.2.1 Pharmacology

4.2.1.1 Primary Pharmacodynamics

4.2.1.2 Secondary Pharmacodynamics

4.2.1.3 Safety Pharmacology

4.2.1.4 Pharmacodynamic Drug Interactions

4.2.2 Pharmacokinetics

4.2.2.1 Analytical Methods and Validation Reports (if separate reports areavailable)

4 2 2 2 Ab ti


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4.2.3.4.2 Short- or medium-term studies (including range-findingstudies that cannot appropriately be included under repeat-dose toxicity or pharmacokinetics)

4.2.3.4.3 Other studies

4.2.3.5 Reproductive and Developmental Toxicity (including range- findingstudies and supportive toxicokinetics evaluations) (If modified studydesigns are used, the following sub-headings should be modifiedaccordingly.)

4.2.3.5.1 Fertility and early embryonic development

4.2.3 .5.2 Embryo-fetal development

4.2.3 .5.3 Prenatal and postnatal development, including maternalfunction

4.2.3 .5.4 Studies in which the offspring (juvenile animals) are dosedand/or further evaluated.


4.2.3.7 Other Toxicity Studies (if available)

4.2.3 .7.1 Antigenicity

4.2.3.7.2 Immunotoxicity

4.2.3 .7.3 Mechanistic studies (if not included elsewhere)

4.2.3.7.4 Dependence

4.2.3.7.5 Metabolites

4.2.3.7.6 Impurities


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APPENDIXA

Examples of Tables and Figures for Written Summaries

The tables and figures in Appendix A are presented merely as examples. Applicantsshould provide tables and figures using a format appropriate to the product.

Study references should be included in the table or text.

Tables should include statistics, if appropriate.


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Table X

Binding of X and its Major Metabolites and Comparators

to Human X2and X3Receptors

Compound X2

Ki1(nM)

X2

Ki2(nM)

X3

Ki1(nM)

X3

Ki2(nM)

1 538 2730 691 4550

2 2699 1050 2.0 181

3 578 14.4 141 10400

4 20 100 10.7 7.9

5 2100 3.1 281 28

6 7.5 8.4 44 2.8

7 3.11 3.76 1.94 1.93

Ki1 and Ki2 represent the high and low affinity binding sites respectively (Data from Study Number).


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Figure X

Blood pressure following chronic dosing with X to SHRa


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Table X

Model-independent pharmacokinetic parameters for X in mice following single oral doses at 2,

10 and 30 mg/kg [ref]

Parameter

(units)

Parameter value

Sex Males Females

Dose(mg/kg)

2 10 30 2 10 30

Cmax(ng/mL)

4.9 20.4 30.7 5.5 12.9 28.6

Tmax(h) 0.8 0.4 0.3 0.4 0.5 0.3

AUC0-t(ng.h/mL)

21.6 80.5 267 33.3 80 298

AUC0-inf(ng.h/mL)

28.3 112 297 40.2 90 327

Pharmacokinetic parameters were determined in pooled plasma from three animals at eachtime


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Table X

Concentrations of radioactive material in the tissues of male rats after a single intravenousdose of [14C]X at 1.75 mg/kg [refs]

Tissue Concentration (ng equiv.*/g)

1 h 6 h 24 h 48 h 72 h

Blood 105 96.6 2.34 2.34 3.65

Plasma 142 175 3.12 ND ND

Adrenals 656 49.2 14.3 9.63 ND

Bone

marrow

359 31.5 ND ND ND

Brain 116 9.37 ND ND ND

Eyes 124 28.9 4.69 ND ND

Fat 490 44.0 10.2 6.25 5.47

Heart 105 26.6 ND ND ND


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Table X

Excretion of radioactive material following single doses of [14C]X to male rats [refs]

Dose (mg/kg)/ Percentage of administered dose

route Urine Faeces Bile Total

1.75 i.v. 61.3 9.3 30.3 4.1 - 95.2 5.0

1.75 p.o. 57.4 3.8 37.0 3.4 - 95.2 1.5

2 p.o. 72.3 0.8 26.9 1.9 - 99.5 1.1

20 p.o. 23.5 6.3 0.5 0.2 76.0 5.9 100 0.8

220 p.o. 67.1 9.0 24.8 5.0 - 93.3 6.8

Excretion was determined over 168 h period in Wistar rats:Values are means S.D.(n=5); - not assayed; Total includes radioactivity in the carcass and cage washings


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Table X

Comparative pharmacokinetic data and systemic exposure to X following oral administration to mice, rats, dogs and

patients [ref]

Species (formulation) Dose (mg/kg/day) Systemic (plasma) exposure References

Cmax

(ng/mL)

AUC (ng.h/mL)#

Man (tablet) 0.48$ 36.7 557 X

Mouse (solution) 8.8 68.9 (1.9)* 72.7 (0.2)* Y

21.9 267 (7.3)* 207 (0.5)*

43.8 430 (11.7)* 325 (0.7)*

Rat (solution) 50 479 (13.0)* 1580 (2.8)* Z

Dogs (solution) 1.5 5.58 (0.2)* 15.9 (


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Table X

Incidence of Proliferative Interstitial (Leydig) Cell Lesions in Rats [ref]

Dose Groups

Lesion Control 3 mg/kg 30 mg/kg 100 mg/kg

Hyperplasia(only)

x/50 (%) x/50 (%) x/50 (%) x/50 (%)

Adenoma(only)

x/50 (%) x/50 (%) x/50 (%) x/50 (%)

Adenoma +Hyperplasia

x/50 (%) x/50 (%) x/50(%) x/50 (%)

Total* x/50 (%) x/50 (%) x/50 (%) x/50 (%)

* Adenoma and/or Hyperplasia


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APPENDIXB

The Nonclinical Tabulated Summaries - Templates


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The Nonclinical Tabulated Summaries Templates

2.6.3 Pharmacology

2.6.3 .1 Pharmacology : Overview

2.6.3.2 Primary Pharmacodynamics *

2.6.3 .3 Secondary Pharmacodynamics*

2.6.3 .4 Safety Pharmacology

2.6.3.5 Pharmacodynamic Drug Interactions*

2.6.5 Pharmacokinetics

2.6.5.1 Pharmacokinetics: Overview

2.6.5.2 Analytical Methods and Validation Reports*

2.6.5.3 Pharmacokinetics: Absorption after a Single Dose

2.6.5.4 Pharmacokinetics: Absorption after Repeated Doses

2.6.5.5 Pharmacokinetics: Organ Distribution

2.6.5.6 Pharmacokinetics: Plasma Protein Binding

2.6.5.7 Pharmacokinetics: Study in Pregnant or Nursing Animals

2.6.5.8 Pharmacokinetics: Other Distribution Study


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2.6.7.6 Repeat-Dose Toxicity: Non-Pivotal Studies

2.6.7.7 Repeat-Dose Toxicity: Pivotal Studies

2.6.7.8 Genotoxicity: In Vitro2.6.7.9 Genotoxicity: In Vivo

2.6.7.10 Carcinogenicity

2.6.7.11 Reproductive and Developmental Toxicity: Non-Pivotal Studies

2.6.7.12 Reproductive and Developmental Toxicity Fertility and EarlyEmbryonic Development to Implantation (Pivotal)

2.6.7.13 Reproductive and Developmental Toxicity Effects on Embryo-Fetal Development (Pivotal)

2.6.7.14 Reproductive and Developmental Toxicity Effects on Pre- andPostnatal Development, Including Maternal Function (Pivotal)

2.6.7.15 Studies in Juvenile Animalsa


2.6.7.17 Other Toxicity Studies

* : Tabulated Summary is optional. It is preferable to include text tables and figureswith the Nonclinical Written Summary.

a: When a juvenile animal study has been conducted, it should be tabulatedusing the template appropriate for the type of study and located inSection 2.6.7.15.


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2.6.3.1 Pharmacology Overview Test Article: (1)

Type of StudyTestSystem

Method ofAdmiistratio

Testig!acility

Study"um#er(4)

$ocatio%ol. Sectio

Primary Pharmacodyamics (2)

(3)

Secodary Pharmacodyamics

Safety Pharmacology

Pharmacodyamic &rug 'teractios

Notes: (1) International Nonproprietary Name (INN)(2) There should be one line for each pharmacology report, in the same order as the CT! "eports that contain a #$% Compliance

&tatement should be identified in a footnote!(3) T he location of the Technical "eport in the CT should be indicated!(4) 'r "eport Number (on all tables)!


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2.6.3.( Safety Pharmacology(1) Test Article)(2)

OrgaSystems*valuated

Species+Strai

Method ofAdmi.

&osesa

,mg+-g

/ederad "o.per /roup "oteworthy !idigs

GLP0ompliace

Study"um#er,3)

Notes: (1) ll safetypharmacology studies should be summari*ed!(2) International Nonproprietary Name (INN)!(3) 'r "eport Number (on all tables)!

a - Single dose unless specified otherwise.


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2.6..1 Pharmaco-ietics Overview Test Article)(1)



Testig!acility

Study"um#er

$ocatio%ol.Sectio

A#sorptio (2)

(3)

&istri#utio

Meta#olism

*cretio

Pharmaco-ietic &rug 'teractios

Other

Notes: (1) International Nonproprietary Name (INN)!(2) There should be one line for each pharmaco+inetics report, in the same order as the CT! "eports that contain a #$% Compliance

&tatement should be identified in a footnote!(3) The location of the Technical "eport in the CT should be indicated!


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2.6..3 Pharmaco-ietics) A#sorptio after a Sigle &ose Test Article)(1)$ocatio i 0T&) Vol. SectionStudy "o.

Species __________ __________ __________ __________ _________/eder ,M+! + "um#er of aimals (4)

!eedig coditio%ehicle+!ormulatioMethod of Admiistratio&ose ,mg+-gSample ,hole #lood4 plasma4 serum etc.AalyteAssay (2)P5 parameters)

Additioal 'formatio) (3)

Notes: (1) International Nonproprietary Name (INN)!(2) or e-ample, .%$C, $&C /ith 10Clabeled compound!(3) or e-ample, brief te-tual results, species differences, gender differences, dose dependency, or special comments!(4) There should be one column for each study conducted! or comparison, representatie information on humans at the ma-imum recommended dose should be included!


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2.6..( Pharmaco-ietics) A#sorptio after epeated &oses Test Article)

ata may be tabulated as in the format of 2!!4!3 if applicable!5


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Format A

2.6.. Pharmaco-ietics) Orga &istri#utio Test Article)$ocatio i 0T&) Vol. SectionStudy "o.

Species)

/eder ,M+!+"um#er of aimals)!eedig coditio)%ehicle+!ormulatio)Method of Admiistratio)&ose ,mg+-g)adiouclide)Specific Activity)Samplig time)

0ocetratio ,uit

Tissues+orgas T,1 T,2 T,3 T,( T, t1+2

Additioal iformatio)


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Alternate Format B

2.6.. Pharmaco-ietics) Orga &istri#utio Test Article)$ocatio i 0T&) Vol. SectionStudy "o.

Species)/eder ,M+! + "um#er of aimals)!eedig coditio)

%ehicle+!ormulatio)Method of Admiistratio)&ose ,mg+-g)adiouclide)Specific Activity)Aalyte+Assay ,uit)Samplig time)

0t $ast time7poitTissues+orgas coc. T+P1 coc. T+P1 Time A80 t1+2


19Tissue:+9Plasma:


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2.6..6 Pharmaco-ietics) Plasma Protei ;idig Test Article)

Study system)Target etity4 Test system ad method)

Species 0oc. tested < ;oud

Study

"o.

$ocatio i 0T&

%ol. Sectio

Additioal 'formatio)


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2.6..= Pharmaco-ietics) Study i Pregat or "ursig Aimals (1) Test Article) (2)$ocatio i 0T&) Vol. Section

Placetal trasfer Study "o.Species)/estatio day + "um#er of aimals)

%ehicle+!ormulatio)Method of Admiistratio)&ose ,mg+-g)Aalyte)Assay)Time ,hr __________ _________ _________ __________ __________0ocetratio + Amout ,< of dose &am (3)) !etus (3))


$ocatio i 0T&) Vol. Section

*cretio ito mil- Study "o.Species)$actatig date + "um#er of aimals)!eedig coditio)%ehicle+!ormulatio)Method of Admiistratio)&ose ,mg+-g)Aalyte)Assay)Time 9hr: __________ __________ __________ __________ __________0ocetratio) Mil-)

Plasma) Mil- + plasma) "eoates)



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"otes for Ta#le 2.6..=

(1) Even if the data are obtained in reproduction toxicolog studies! the should be presented in this table.(2) "nternational #onproprietar #a$e ("##).(3) %he tissue sa$pled should be described& e.g.! plas$a for da$s! fetal concentrations.


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2.6..> Pharmaco-ietics) Other &istri#utio Study Test Article)


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2.6..? Pharmaco-ietics) Meta#olismIn Vivo Test Article)

/eder,M+! + "um#er of aimals)!eedig coditio)%ehicle+!ormulatio)Method of Admiistratio)&ose ,mg+-g)

adiouclide)Specific Activity)

< of 0ompoud i Sample $ocatio i 0T&

Species SampleSamplig Time or Period

< of &osei Sample Paret M1 M2

Study "o. %ol Sectio

'las$arineile*eces

'las$arineile*eces

'las$arineile*eces


#ote: .uman data should be included for comparison, if aailable!


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2.6..1@ Pharmaco-ietics) Meta#olism In Vitro Test Article)$ocatio i 0T&) Vol. SectionStudy "o.

Study system)

Time __________ __________ __________ __________ __________0ocetratio)0ompouds Paret M71 M72


Note: .uman data should be included for comparison, if aailable!


41/113


2.6..11 Pharmaco-ietics) Possi#le Meta#olic Pathways Test Article)

(Illustrate possible metabolic map indicating species in /hich metabolic reactions occur!)


42/113


2.6..12 Pharmaco-ietics) 'ductio+'hi#itio of &rug7Meta#oliig *ymes Test Article)$ocatio i 0T&) Vol. SectionStudy "o.

Note: Nonclinical studies only!

Type of study)

Method)

Ta#ulated results)



43/113


2.6..13 Pharmaco-ietics) *cretio Test Article) (1)

Species __________ __________ __________ _________

/eder ,M+! + "um#er of aimals (3)

!eedig coditio

%ehicle+!ormulatio

Method of Admiistratio

&ose ,mg+-g

Aalyte

Assay

*cretio route (4) 8rie !eces Total 8rie !eces Total 8rie !eces Total 8rie !eces Total Time @ 7 T hr

Study um#er

$ocatio i 0T&

Additioal 'formatio) (2)

Notes: (1) International Nonproprietary Name (INN)!(2) or e-ample, brief te-tual results, species differences, gender differences, dose dependency, or special comments!(3) There should be one column for each study conducted! or comparison, representatie information on humans at the ma-imum

recommended dose should be included! 6ay be combined /ith the bsorption Table, if appropriate!(4) 'ther routes (e!g!, biliary, respiratory) should be added, if performed!


44/113


2.6.5.14 Pharmacokinetic! "#cretion into Bile $et Article!

ata may be tabulated as in the format of 2!!4!13 if applicable!5


45/113


2.6..1 Pharmaco-ietics) &rug7&rug 'teractios Test Article)$ocatio i 0T&) Vol. SectionStudy "o.

Type of study)

Method)

Ta#ulated results)



46/113


2.6.5.16 Pharmacokinetic! %ther Test Article)$ocatio i 0T&) Vol. SectionStudy "o.

Type of study)

Method)

Ta#ulated results)



47/113


2.6.=.1 Toicology Overview Test Article) (1)

Type of StudySpecies adStrai


&uratioof &osig &oses ,mg+-ga

/$P0ompliac

e

Testig!acility

Study"um#er

$ocatio%ol.

Sectio

Sigle7&oseToicity

(2) (3)

epeat7&oseToicity

/eotoicity

0arciogeicity

eproductive ad&evelopmetalToicity

$ocal Tolerace

OtherToicity Studies

Notes: (1) International Nonproprietary Name (INN)!(2) There should be one line for each to-icology report, in the same order as the CT!(3) The location of the Technical "eport in the CT should be indicated!

a - nless otherwise specified. *or +epeat-,ose %oxicit! the highest #E/ (#o bserved dverse-Effect /evel) is underlined.


48/113


2.6.=.2 Toico-ietics Overview of Toico-ietics Studies Test Article) (1)


Method ofAdmiistratio &oses ,mg+-g

/$P0ompliace

Study"um#er

$ocatio%ol.Sectio

(2) (3)

Notes: (1) International Nonproprietary Name (INN)!(2) There should be one line for each to-ico+inetics report, in the same order as the CT (&ection 3, To-icology)!(3) The location of the Technical "eport in the CT should be indicated!


49/113


2.6.=.3 Toico-ietics Overview of Toico-ietics &ata Test Article) (1)

(2)

Notes: (1) International Nonproprietary Name (INN)!(2) one to threepage summary (tables and7or figures) of steadystate to-ico+inetic data should be prepared in a format that facilitates

comparisons across species, including humans!


50/113


2.6.=.( Toicology &rug Su#stace Test Article) (1)

;atch "o. Purity ,


51/113


2.6.=. Sigle7&ose Toicity (1) Test Article)(2)

Species+Strai

Method ofAdmiistratio,%ehicle+!ormulatio

&oses,mg+-g

/ederad "o.per /roup

O#servedMaimum "o7$ethal &ose,mg+-g

Approimate$ethal&ose ,mg+-g "oteworthy !idigs

Study"um#er

Notes: (1)ll singledose to-icity studies should be summari*ed, in the same order as the CT! ootnotes should be used to indicate specialfeatures, such as unusual duration, infusion rate, or age of test sub8ects!

(2) International Nonproprietary Name (INN)!


52/113


2.6.=.6 epeat7&ose Toicity "o7Pivotal Studies(1) Test Article)(2)

Species+Strai

Method ofAdmiistratio,%ehicle+

!ormulatio

&uratioof &osig

&oses,mg+-g


"OA*$a

,mg+-g "oteworthy !idigsStudy"um#er

Notes: (1) ll repeatdose to-icity studies (including all rangefinding to-icity studies), other than the definitie #$% studies specified by IC.

#uideline 63, should be summari*ed, in the same order as the CT! ootnotes should be used to indicate special features, such asunusual age of test sub8ects!

(2) International Nonproprietary Name (INN)!

________a - #o bserved dverse-Effect /evel.


53/113


2.6.=.= (1)epeat7&ose Toicity(2) eport Title) Test Article)(3)

Species+Strai) &uratio of &osig) Study "o.'itial Age) &uratio of Postdose) $ocatio i 0T&)Vol. Section&ate of !irst &ose) Method of Admiistratio)

%ehicle+!ormulatio) /$P 0ompliace)

Special !eatures)"o O#served Adverse7*ffect $evel)

&aily &ose ,mg+-g (0ontrol)"um#er of AimalsToico-ietics) A80 , (4)"oteworthy !idigs&ied or Sacrificed Mori#ud;ody eight ,


54/113


2.6.=.= (1)epeat7&ose Toicity Study "o. ,0otiued

&aily &ose ,mg+-g (0ontrol)"um#er of Aimals 2: *: 2: *: 2: *: 2: *:

Bematology

Serum 0hemistry

8rialysis

Orga eightsa ,


55/113


#otes for %able 8.9..

(1) %he tables should be nu$bered consecutivel: 8.9..! 8.9..! 8.9..0 etc.

(2) %here should be one table for each of the repeat-dose toxicit studies specified b "0;


56/113


2.6.=.> (1)/eotoicity) ' %itro eport Title) Test Article) (2)

Test for 'ductio of) "o. of 'depedet Assays) Study "o.Strais) "o. of eplicate 0ultures) $ocatio i 0T&)Vol. SectionMeta#oliig System) "o. of 0ells Aalyed+0ulture)%ehicles) !or Test Article) !or Positive 0otrols) /$P 0ompliace)

Treatmet) &ate of Treatmet)0ytotoic *ffects)/eotoic *ffects)

2etabolicctivation

%estrticle

0oncentration or,ose /evel( (3) ) _____________ _____________ _____________ ____________ _____________

?ithoutctivation

(0)?ith

ctivation

Notes: (1) The tables should be numbered consecutiely: 2!!9!, 2!!9!


57/113


2.6.=.? (1)/eotoicity) ' %ivo eport Title) Test Article) (2)

Test for 'ductio of) Treatmet Schedule) Study "o.Species+Strai) Samplig Time) $ocatio i 0T&)Vol. SectionAge) Method of Admiistratio)0ells *valuated) %ehicle+!ormulatio) /$P 0ompliace)

"o. of 0ells Aalyed+Aimal) &ate of &osig)Special !eatures)Toic+0ytotoic *ffects)/eotoic *ffects)*videce of *posure)

%est rticle,ose($g@4g)

#o. ofni$als ______________ ______________ ______________ _____________

Notes: (1) The tables should be numbered consecutiely: 2!!9!;, 2!!9!;


58/113


2.6.=.1@ (1)0arciogeicity eport Title) Test Article) (2)

Species+Strai) &uratio of &osig) Study "o.'itial Age) Method of Admiistratio) $ocatio i 0T&)Vol. Section&ate of !irst &ose) %ehicle+!ormulatio)

Treatmet of 0otrols) /$P 0ompliace)

;asis for Bigh7&ose Selectio) (3)Special !eatures)

&aily &ose ,mg+-g (0ontrol)

/ederToico-ietics) A80 , (4)"um#er of AimalsAt Start&ied+Sacrificed Mori#udTermial SacrificeSurvival ,


59/113


2.6.=.1@ (1)0arciogeicity Study "o. ,0otiued

&aily &ose ,mg+-g (0ontrol) (0ontrol)"um#er *valuated"um#er of Aimals

with "eoplastic $esios) (')"oteworthy !idigs)/ross PathologyBistopathology 7 "o7"eoplastic$esios

2: *: 2: *: 2: *: 2: *: 2: *:

- #o noteworth findings.5 - p6.7 55 - p6.1

Th C T h i l D t S f t


60/113


#otes for %able 8.9..1.

(1) %ables should be nu$bered consecutivel: 8.9..1! 8.9..1! ! etc. %here should be one table for each carcinogenicit stud.

(2) "nternational #onproprietar #a$e ("##).

(3) *ro$ "0;


61/113

The Common Technical Document Safety


62/113


2.6.=.12 (1)eproductive ad &evelopmetal Toicity 7 eport Title ) Test Article) (2)!ertility ad *arly *m#ryoic&evelopmet to 'mplatatio (3)

&esig similar to '0B (.1.1C &uratio of &osig) 2: Study "o.Species+Strai) &ay of Matig) (&) *: $ocatio i 0T&)Vol. Section'itial Age) &ay of 07Sectio)

&ate of !irst &ose) Method of Admiistratio) /$P 0ompliace)Special !eatures) %ehicle+!ormulatio)"o O#served Adverse7*ffect $evel)

!@Males)!@!emales)!1$itters)

&aily &ose ,mg+-g @ ,0otrol

Males %oxico4inetics: 0 ( ) (0)

#o. Evaluated#o. ,ied or Sacrificed 2oribund0linical bservations#ecrops bservationsod ?eight (Aa)*ood 0onsu$ption (Aa)2ean #o. ,as 'rior to 2ating#o. of 2ales that 2ated#o. of *ertile 2ales (4)

- #o noteworth findings. 3 2ild 332oderate 3332ar4ed ()(9)5 - p6.7 55 - p6.1

a - fter B wee4s of dosing. *or controls! group $eans are shown. *or treated groups! percent differences fro$ controls are shown. Statisticalsignificance is based on actual data (not on the percent differences).

(0ontinued)

59



63/113


2.6.=.12 (1)eproductive ad &evelopmetal Toicity Study "o. ,0otiued


!emales %oxico4inetics: 0 ( ) (0)

#o. Evaluated#o. ,ied or Sacrificed 2oribund0linical bservations#ecrops bservations're$ating od ?eight (Aa)


64/113


#otes for %ables 8.9..18! 8.9..1= and 8.9..1B

(1) "f there are $ultiple studies of this tpe! the tables should be nu$bered consecutivel: 8.9..18! 8.9..18! 8.9..1=! 8.9..1=! etc.

(2) "nternational #onproprietar #a$e ("##).

(3) "f a $odified stud design is used! tables should be $odified accordingl.

(4) Stead-state 0! 0$ax! or other toxico4inetic infor$ation supporting the stud. "f the infor$ation is fro$ a separate stud! the Stud #u$bershould be given in a footnote.

(5) 'SS"/E '+ESE#%%"#S * %;E +ES/%S +E S;?# "# %;ESE %E2'/%ES. ,% '+ESE#%%"# S;/, E */EC"/E#, ''+'+"%E 00+,"#< % '%"2/ S%%"S%"0/ #/>S"S #, %;E ,ES". "f additional para$etersshowed drug-related changes! these should be added to the tables. *ootnotes should be used as needed to provide additional infor$ation aboutthe tests or the results.

(6) r other scale as appropriate.

(9) 2ethods of statistical analsis should be indicated.

() ,a of $ating should be indicated& e.g.! ,a or ,a 1

61



65/113


2.6.=.13 (1)eproductive ad &evelopmetal Toicity 7 eport Title) Test Article) (2)*ffects o *m#ryo7!etal&evelopmet (3)

&esig similar to '0B (.1.3C &uratio of &osig) Study "o.&ay of Matig) (&)

Species+Strai) &ay of 07Sectio) $ocatio i 0T&)Vol. Section'itial Age) Method of Admiistratio)&ate of !irst &ose) %ehicle+!ormulatio) /$P 0ompliace)Special !eatures)"o O#served Adverse7*ffect $evel)

!@!emales)!1$itters)


&ams+&oes) %oxico4inetics: 0 ,(0)

#o. 'regnant#o. ,ied or Sacrificed 2oribund#o. borted or with %otal +esorption of /itter0linical bservations#ecrops bservationsod ?eight (Aa)*ood 0onsu$ption (Aa)2ean #o. 0orpora /utea2ean #o. "$plantations2ean A 'rei$plantation /oss

(4)

- #o noteworth findings. 3 2ild 332oderate 3332ar4ed () < D


66/113


2.6.=.13 (1)eproductive ad &evelopmetal Toicity Study "o. ,0otiued


/itters: #o. /itters Evaluated#o. /ive *etuses

2ean #o. +esorptions#o. of /itters with ,ead *etuses2ean A 'osti$plantation /oss2ean *etal od ?eight (g)*etal Sex +atios*etal no$alies:


67/113

he Common echnical ocument Safety

2.6.=.1( (1)eproductive ad &evelopmetal Toicity 7 eport Title) Test Article) (2)*ffects o Pre7 ad Postatal&evelopmet4 'cludig Materal !uctio (3)

&esig similar to '0B (.1.2C &uratio of &osig) Study "o.&ay of Matig) (&)

Species+Strai) Method of Admiistratio) $ocatio i 0T&)Vol. Section'itial Age %ehicle+!ormulatio)&ate of !irst &ose) $itters 0ulled+"ot 0ulled) /$P 0ompliace)Special !eatures)"o O#served Adverse7*ffect $evel)

!@!emales)!1Males)!1!emales)


**e$ales: %oxico4inetics: 0 ( ) (0)

#o. 'regnant#o. ,ied or Sacrificed 2oribund#o. borted or with %otal +es. f /itter0linical bservations#ecrops bservations


68/113

f y

2.6.=.1( (1)eproductive ad &evelopmetal Toicity Study "o. ,0otiued


*1/itters:('reweaning)

*12ales:

('ostweaning)

#o. /itters Evaluated2ean #o. of "$plantations

2ean #o. 'ups@/itter2ean #o. /iveborn 'ups@/itter#o. of /itters with Stillborn 'ups'ostnatal Survival to ,a B'ostnatal Survival to ?eaning#o. of %otal /itter /osses0hange in 'up od ?eightsa(g)'up Sex +atios'up 0linical Signs'up #ecrops bs.

#o. Evaluated 'ostweaning'er /itter

#o. ,ied or Sacrificed 2oribund0linical bservations#ecrops bservationsod-?eight 0hangeb(g)*ood 0onsu$ption (Ac)'reputial SeparationSensor *unction2otor ctivit/earning and 2e$or2ean #o. ,as 'rior to 2ating#o. of 2ales that 2ated#o. of *ertile 2ales

- #o noteworth findings. 3 2ild 332oderate 3332ar4ed ()(9)5 - p6.7 55 - p6.1a - *ro$ birth to weaning.b - *ro$ weaning to $ating.c - t end of postweaning period. *or controls! group $eans are shown. *or treated groups! percent differences fro$ controls are shown.

Statistical significance is based on actual data (not on the percent dif ferences).

65



69/113

f y



*1*e$ales:('ostweaning)

*8/itters:

#o. Evaluated 'ostweaning#o. ,ied or Sacrificed 2oribund

0linical bservations#ecrops bservations're$ating od-?eight 0hangea(g)


70/113



*1*e$ales:('ostweaning)

*8/itters:

#o. Evaluated 'ostweaning#o. ,ied or Sacrificed 2oribund0linical bservations

#ecrops bservations're$ating od-?eight 0hangea(g)


71/113

2.6.=.16 $ocal Tolerace (1) Test Article)(2)

Species+Strai


&oses,mg+-g

/eder ad"o. per /roup "oteworthy !idigs

Study"um#er

Notes: (1) ll localtolerance studies should be summari*ed!(2) International Nonproprietary Name (INN)!

68



72/113

2.6.=.1= Other Toicity Studies (1) Test Article)(2)

Species+Strai


&uratioof &osig

&oses,mg+-g


Study"um#er

Notes: (1)ll supplementary to-icity studies should be summari*ed!(2) International Nonproprietary Name (INN)!

69


73/113


APPENDIXC

The Nonclinical Tabulated Summaries - Examples



74/113

EC2'/E

2.6.3.1 Pharmacology Overview Test Article) 0uritol Sodiu$



Testig!acility

Study"um#er

$ocatio%ol. Sectio

1.1 Primary Pharmacodyamicsntiviral activit vs. VVntiviral activit vs. VVntiviral activit vs. ;SVntiviral activit vs. 02Vntiviral activit vs. VVntiviral activit vs. SVV

;u$an e$bronic lungfibroblasts0linical isolates;u$an e$bronic lungfibroblasts;u$an e$bronic lungfibroblasts"0+ $ice

frican


75/113



76/113

2.6..1 Pharmaco-ietics Overview Test Article) 0uritol Sodiu$

Type of Study

TestSystem


Testig!acility

Study"um#er

$ocatio%ol.Sectio

A#sorptiobsorption and excretionbsorption and excretionbsorption and excretion

+ats,ogs2on4es


77/113

2.6..3 Pharmaco-ietics) A#sorptio after a Sigle &ose Test Article) 0uritol Sodiu$$ocatio i 0T& Volu$e 1! SectionStudy um#er F71B

Species Mouse at &og Mo-ey Buma/eder ,M+! + "um#er of aimals B2 =2 B* 82 92!eedig coditio *ed *asted *asted *ed *asted%ehicle+!ormulatio Suspension

1A acaciaSuspension1A acacia

0apsule Suspension1A acacia

%ablet

Method of Admiistratio


78/113

Format A

2.6.. Pharmaco-ietics) Orga &istri#utio Test Article) 0uritol Sodiu$

$ocatio i 0T&) Vol. 81! SectionStudy "o. F78

Species) +at/eder ,M+!+"um#er of aimals) =2@each ti$e point!eedig coditio) *asted%ehicle+!ormulatio) Solution@?aterMethod of Admiistratio) ral


79/113

Alternate Format B

2.6.. Pharmaco-ietics) Orga &istri#utio Test Article) 0uritol Sodiu$

$ocatio i 0T&) Vol. 81! SectionStudy "o. F78

Species) +at/eder ,M+! + "um#er of aimals) =2@each ti$e point!eedig coditio) *ed%ehicle+!ormulatio) Solution@SalineMethod of Admiistratio) "ntravenous

&ose ,mg+-g) 1adiouclide) #on-labeled co$poundSpecific Activity) 7Aalyte+Assay) nchanged co$pound ($cg@$/)@;'/0

Samplig time) 1 $in! 1! B! G! 8B! BG! F9! and 19G hr 01hr $ast time7poitTissues+orgas coc. T+P1 coc. T+P1 Time A80 t1+2

Beart 1.B .G .BB 88 BG 7.= =.=$iver B.7 9 1.G7 F8.7 BG 8F 71.5idey 8.G .8 1. 7=.7 BG 189 =9.=Splee 9.7 G.9 =.7 17 BG B1 B9.F


19Tissue:+9Plasma:

EC2'/E

77



80/113

2.6..6 Pharmaco-ietics) Protei ;idig Test Article) 0uritol Sodiu$

Study system) "n vitroTarget etity4 Test system ad method) 'las$a!ltrafiltration

Species 0oc. tested < ;oud

Study "o.

$ocatio i 0T& %ol. Sectio

at 1 - 1u2 G8.1 - G7.B F7=1 81

&og 1 - 1u2 G=.7 - GG.8 F7=1 81

Buma 1 - 1u2 7.8 - F.B F9-1=-= B7


78

EC2'/E



81/113

2.6..= Pharmaco-ietics) Study i Pregat or "ursig Aimals Test Article) 0uritol Sodiu$

$ocatio i 0T&) Vol. 88! SectionPlacetal trasfer Study "o.F78Species) +at/estatio day + "um#er of aimals) 1B and 1F das gestation@= ani$als at each ti$e point%ehicle+!ormulatio) Solution@?aterMethod of Admiistratio) ral gavage&ose ,mg+-g) 7Aalyte) %otal radioactivit! 1B0

Assay) /S0Time ,hr 1( days+3@ mi 1( days+2( hr 1? days+3@ mi 1? days+2( hr 0ocetratio + Amout ,< of dose

Materal plasma 18.B .=8 1=.F .=8Placeta =.G .1B =.= .=8Amiotic fluid . .B .B .1=hole fetus .7B .= .=F .1

Additioal 'formatio)2aternal blood! liver! 4idne! ovar! uterus were also exa$ined but not shown.

$ocatio i 0T&) Vol. 88 Section*cretio ito mil- Study "o. F7=Species) +at$actatig date + "um#er of aimals) da @=!eedig coditio) *ed%ehicle+!ormulatio) Solution@?ater

Method of Admiistratio) ral gavage&ose ,mg+-g) 7Aalyte) %otal radioactivit! 1B0Assay) /S0

Time 9hr: 1 2 ( 6 > 2(0ocetratio)

Mil-) .9 .G 1. 1.1 1.= .B

Plasma) 1.7 1.B 1.8 .G .9 .1

Mil- + plasma) .B .7 .G= 1.B 8.8 B.

"eoates


EC2'/E

79



82/113

2.6..? Pharmaco-ietics) Meta#olism In Vivo Test Article) 0uritol Sodiu$

/eder ,M+! + "um#er of aimals) ats) B2 &ogs) =* Bumas) G2!eedig coditio) *ed%ehicle+!ormulatio) ats) Solution@water &ogs) 0apsules Bumas) 7-$g tabletsMethod of Admiistratio) ats)


83/113

2.6..13 Pharmaco-ietics) *cretio Test Article) 0uritol Sodiu$

Species +at +at ,og ,og/eder ,M+! + "um#er of aimals B2 B2 =2 =2!eedig coditio *asted *asted *asted *asted%ehicle+!ormulatio Solution

?ater

Solution

Saline

0apsule Solution

SalineMethod of Admiistratio ral "ntravenous ral "ntravenous&ose ,mg+-g 1 7 1 7Aalyte %+a %+a %+a %+a

Assay /S0 /S0 /S0 /S0*cretio route 8rie !eces Total 8rie !eces Total 8rie !eces Total 8rie !eces Total Time

@ 7 2( hr@ 7 (> hr@ 7 =2 hr@ 7 ?6 hr

89==1=1

797979

G=F7FFG

8888G8F

9=9F

G7F9FGFF

8878989

8F97=B

BFFFF

1

8=8G8F8F

B8G8=

97F91118

Study um#er F718 F7179$ocatio i 0T& Volu$e 8! Section Volu$e 8! Section


a - %otal radioactivit& percent recover!1B

0

EC2'/E

81


EC2'/E


84/113

2.6..1( Pharmaco-ietics) *cretio ito ;ile Test Article) 0uritol Sodiu$

Species at at/eder ,M+! + "um#er of aimals B2 B2!eedig coditio *asted *asted%ehicle+!ormulatio Solution

?ater

Solution

SalineMethod of Admiistratio ral "ntravenous&ose ,mg+-g 1 7Aalyte %+a %+a

Assay /S0 /S0*cretio route ;ile 8rie Total ;ile 8rie Total Time @ 7 2 hr

@ 7 ( hr@ 7 > hr@ 7 2( hr@ 7 (> hr

=798FG=

---F1

=798G9F=

7G8G9GGG

---

1111

7G8G9FGFF

Study um#er F719$ocatio i 0T& Volu$e 8! Section

a 7 Total radioactivityF percet recovery4 1(0

82

EC2'/E


EC2'/E


85/113

2.6.=.1 Toicology Overview Test Article)0uritol Sodiu$

Type of StudySpecies adStrai


&uratioof &osig &oses ,mg+-ga

/$P0ompliace

Testig!acility

Study"um#er

$ocatio%ol.Sectio

Sigle7&oseToicity

0,-1 2ice

?istar +ats

es

>es

>es>es

Sponsor "nc.

0+ 0o.

Sponsor "nc.0+ 0o.

F9B9

F9B

F97F971

1

1

11

epeat7&oseToicity

0,-1 2ice

?istar +ats

eagle ,ogs

0no$olgus2on4es

,iet

,ietes>es

#o

0+ 0o.

Sponsor "nc.Sponsor "nc.Sponsor "nc.

Sponsor "nc.

Sponsor "nc.Sponsor "nc.

0+ 0o.

FB1G

FB1FFBFB81B

F71

FB8F9B1

FBG

8

==B

7

9

G

/eotoicity S.tphi$uriu$and E. coli

;u$an/$phoctes

?istar +ats

"n Vitro

"n Vitro

es

>es

>es

Sponsor "nc.

0+ 0o.

Sponsor "nc.

F91G

F9=B

F9=

F

F

F

a - nless otherwise specified. *or Single-,ose %oxicit and +epeat-,ose %oxicit! the highest #E/ (#o bserved dverse-Effect /evel)is underlined.

(0ontinued)

EC2'/E


EC2'/E


86/113

2.6.=.1 Toicology Overview ,0otiued Test Article)0uritol Sodiu$

Type of Study

Species adStrai


&uratioof &osig &oses ,mg+-g

/$P0ompliace

Testig!acility

Study"um#er

$ocatio%ol.Sectio

0arciogeicity 0,-1 2ice

?istar +ats

,iet

es

>es

0+ 0o.

Sponsor "nc.

F718

F71=

1

18

eproductioToicity

?istar +ats?istar +ats#? +abbits?istar +ats


87/113

EC2'/E

2.6.=.2 Toico-ietics Overview of Toico-ietics Studies Test Article) 0uritol Sodiu$


Method ofAdmiistratio &oses ,mg+-g

/$P0ompliace

Study"um#er

$ocatio%ol. Sectio

%hree-$onth range-finding stud%wo-wee4 toxicit studSix-$onth toxicit studne-$onth toxicit stud#ine-$onth toxicit stud0arcinogenicit stud0arcinogenicit stud%oxico4inetics stud

2ice+ats+ats,ogs,ogs2ice+ats+abbits

,ietes>es>es#o

FB1GFBF71FB8F9B1F718F71=F8=1

8 = 7 9 11819

85


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2.6.=.3 Toico-ietics Overview of Toico-ietics &ata Test Article)0uritol Sodiu$

Steady7State A80 ,mcg7hr+ml

&aily &ose,mg+-g)

Micea

M !ats#

M ! &ogsc!emalea##its# Bumasf

1 7 1 8 87 B

1 18 9 G

= B1

1

F 87

8=

=

798.7187=B

=7 B18

G17

B BG 1=7

7

87d! 8e

9G F

8d! 88e

8 G7

18

B

7F18B

8!1=

B!F7G!8B1

1!G

=!FG!9G

187 8 87 =8

18 1F 8B =81

__________a - "n diet.b - gavage.

c - "n capsules. 2ales and fe$ales co$bined.d - Six-$onth toxicit stud.e - 0arcinogenicit stud.f - 'rotocol 1B-.

86

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*GAMP$*

2.6.=.3 Toico-ietics Overview of Toico-ietics &ata Test Article ) 0uritol Sodium

.1

1

1

1

1

.1 .1 1 1 1

&ose ,mg+-g.

;u$ans

2ale 2ice

*e$ale 2ice

2ale +ats

*e$ale +ats

,ogs

Stead-state 08Bhrvalues of unchanged 22-1GG1 in hu$ans after repeated oral ad$inistration of 1! 8.7! and 7 $g ,! in co$parison with thosein $ice in the carcinogenicit stud! rats in the 9-$onth toxicit stud! and dogs in the F-$onth toxicit stud.

A80

2(hr

,ughr+ml.

87


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2.6.=.( Toicology &rug Su#stace Test Article) 0uritol Sodiu$

;atch "o. Purity ,


91/113

2.6.=. Sigle7&ose Toicity Test Article)0uritol Sodiu$

Species+Strai

Method ofAdmiistratio,%ehicle+!ormulatio

&oses,mg+-g


O#servedMaimum "o7$ethal &ose,mg+-g

Approimate$ethal&ose ,mg+-g "oteworthy !idigs

Study"um#er

0,-1 2ice


92/113

2.6.=.6 epeat7&ose Toicity "o7Pivotal Studies Test Article)0uritol Sodiu$

Species+Strai

Method ofAdmiistratio,%ehicle+

!ormulatio

&uratioof &osig

&oses,mg+-g


"OA*$a

,mg+-g "oteworthy !idigsStudy"um#er

0,-1 2ice ,iet = 2onths ! 98.7!87! 1!B! and

12! 1* 2:B*: 1

B: /ower bod weights& gastric

erosions@ulcers in so$e $ice.: B2 and 9* died@ sacrificed&lower bod weights& single-cell necrosisin liver.

FB1G

?istar+ats

,iet


93/113

2.6.=.=A epeat7&ose Toicity eport Title) 22-1GG1: %hree-2onth ral %oxicit Stud in +ats Test Article)0uritol Sodiu$

Species+Strai)?istar +ats &uratio of &osig)= 2onths Study "o.FB81B'itial Age)7 ?ee4s &uratio of Postdose)1 2onth $ocatio i 0T&)Vol. B! Section&ate of !irst &ose)17 Kan FB Method of Admiistratio)esSpecial !eatures)#one

"o O#served Adverse7*ffect $evel)8 $g@4g

&aily &ose ,mg+-g (0ontrol) 8 9 1G"um#er of AimalsToico-ietics) A80 ,mcg7hr+ml)&ay 1&ay 2>&ay ?@"oteworthy !idigs&ied or Sacrificed Mori#ud;ody eight ,


94/113

2.6.=.=A epeat7&ose Toicity Study "o. ?(21( ,0otiued

&aily &ose ,mg+-g (0ontrol) 8 9 1G

"um#er of Aimals

Bematology

Bemoglo#i ,g+dl*rythrocyte 0out ,1@6+mm3

M0B

M0B0

Platelet 0out ,1@3+mm3

Serum 0hemistry

0reatiie ,'8+$

Proteis g+dl

0holesterol ,mg+dl

A$T ,'8+$

AST ,'8+$

;iliru#i ,mg+dl

0alcium ,m*D+$

Phosphorus ,m*D+$

8rialysis

Protei 0oc. ,mg+dl

pB

/lucose ,mg+dl

8rie %olume ,ml

2:=

17.GG.1

-

-

GB9

.

-

F9

9

GG

.1G

-

F.=

89

.7

-

-

*:=

17.-

88

=B

FF

.

9.

-

79

F8

.8

1.

-

BF

-

1G

2:8

17..F

-

-

G87

.

-

G9

95

F9

.1

-

F.=

18

.7

-

-

*:8

1B.F-

81

=B

G1B

.

9.9

-

78

F

.8

1.G

-

=B

-

1G

2:8

17.GG.1

-

-

F1B

.

-

F

775

G5

.1G

-

F.=

18=

.8

-

-

*:8

1B.9-

88

=B

G79

.

9.9

-

B5

GB5

.8

1.G

-

7B

-

8

19

2:=

1B.5.B5

-

-

F=15

1.15

-

175

7=5

G75

.8855

-

G.85

1895

9.=55

-

-

*:=

1=.15-

1F5

=5

F115

1.15

7.55

-

7G

F=

.8955

F.G55

-

885

-

FG55

185

- #o noteworth findings.,unnettLs %est: 5- p6.7 55- p6.1

(0ontinued)

92


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2.6.=.=; epeat7&ose Toicity eport Title) 22-1GG1:ne-2onth ral %oxicit Stud in ,ogs Test Article)0uritol Sodiu$

Species+Strai)eagle ,ogs &uratio of &osig)1 2onth Study "o.FB8'itial Age)7-9 2onths &uratio of Postdose)#one $ocatio i 0T&)Vol. 9! Section&ate of !irst &ose)8 *eb FB Method of Admiistratio)ral

%ehicle+!ormulatio)esSpecial !eatures);epatic enN$e induction evaluated at ter$ination.

"o O#served Adverse7*ffect $evel)1 $g@4g

&aily &ose ,mg+-g (0ontrol) 1 B 1

"um#er of Aimals

Toico-ietics) A80 ,mcg7hr+ml)

&ay 1

&ay 2>

"oteworthy !idigs

"o. &ied or Sacrificed Mori#ud

;ody eight ,A /eotoicity) ' %itro eport Title) 22-1GG1: $es +everse-2utation Stud in Test Article) 0uritol Sodiu$ Sal$onella and E. 0oli

Test for 'ductio of)+everse $utation in bacterial cells "o. of 'depedet Assays)8 Study "o.F999FStrais)S. tphi$uriu$ and E. coli "o. of eplicate 0ultures)= $ocatio i 0T&)Vol. 1! SectionMeta#oliig System)roclor-induced rat liver SF4.1A "o. of 0ells Aalyed+0ulture)-%ehicles) Test Article),2S Positive 0otrols),2S /$P 0ompliace)>esTreatmet)'late incorporation for BG hr. &ate of Treatmet)*eb. 1FF9

0ytotoic *ffects) #one./eotoic *ffects)#one.

2etabolicctivation

%estrticle

,ose /evel($cg@plate)

ssa M1+evertant 0olon 0ounts (2ean OS,)

% FG % 1 % 17=7 % 17= ?'8 uvr

?ithoutctivation

,2S22-1GG1

8-#itrofluoreneSodiu$ aNideF-$inoacridine22S

1 $cl@plate=18.7987187877a

8118.7 $cl@plate

8B O F8B O 9=8 O F= O B8 O 7= O =9F9

18F O B18G O 1117= O F178 O 181B O 91= O 81

7B8

17 O B18 O BF O 8F O =F O =17 O 1

B9G

B O 8B O 8G O 8F O 87 O 1 O 8

717

1 O =1B O 81 O 71G O B1F O 11= OB

7=

?ithctivation

,2S22-1GG1

8-$inoanthracene

1 $cl@plate=18.798718787

7

a

8.71

8 O 9=1 O B= O 1== O 8=7 O G

=1 O B1778

191 O 181B8 O G179 O 1717= O 1=19 O B

17= O 71BG

18 O 718 O 71 O 81= O =1 O 8

F O B81B

7 O 1B O 8F O 7G O 8G O 8

O 191

81 O G1 O =8= =1G O =1F O 7

1 OB

=99a - 'recipitation.

96


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2.6.=.?A /eotoicity) ' %ivo eport Title) 22-1GG1: ral 2icronucleus Stud in +ats Test Article) 0uritol Solution

Test for 'ductio of)one-$arrow $icronuclei Treatmet Schedule)%hree dail doses. Study "o)F99G=Species+Strai)?istar +ats Samplig Time)8B hr after last dose. $ocatio i 0T&)Vol. 1! SectionAge)7 ?ee4s Method of Admiistratio)


101/113

2.6.=.?; /eotoicity) ' %ivo eport Title) 22-1GG1: ral ,# +epair Stud in +ats Test Article) 0uritol Solution

Test for 'ductio of)nscheduled ,# snthesis Treatmet Schedule)Single dose. Study "o)71FSpecies+Strai)?istar +ats Samplig Time)8 and 19 hr. $ocatio i 0T&)Vol. 11! SectionAge)7 ?ee4s Method of Admiistratio)es"o. of 0ells Aalyed+Aimal)1 &ate of &osig)Kan. 1FF

Special !eatures)#one.Toic+0ytotoic *ffects)#one./eotoic *ffects)#one.*videce of *posure)%oxico4inetics - See Stud #o. FB! %wo-?ee4 ral %oxicit Stud in +ats.

%est rticle,ose

($g@4g)#o. of

ni$als%i$e hr

#uclear2ean O S,

0toplas$2ean O S,

#es &uratio of &osig)


109/113

2.6.=.13 eproductive ad &evelopmetal Toicity Study "o. ?=@2>,0otiued

&aily &ose ,mg+-g @ ,0otrol 1 2

/itters: #o. /itters Evaluated#o. /ive *etuses

2ean #o. +esorptions#o. ,ead *etuses2ean A 'osti$plantation /oss2ean *etal od ?eight (g)*etal Sex +atios (A $ales)*etal no$alies:


110/113


2 6 = 1( eproductive ad &evelopmetal Toicity Study "o ?2@1

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2.6.=.1( eproductive ad &evelopmetal Toicity Study "o. ?2@1,0otiued

&aily &ose ,mg+-g @ ,0otrol =. = =@

*1/itters:('reweaning)

*12ales:('ostweaning)

#o. /itters Evaluated2ean #o. 'ups@/itter

2ean #o. /iveborn 'ups@/itter2ean #o. Stillborn 'ups@/itter'ostnatal Survival to ,a B'ostnatal Survival to ?eaning0hange in 'up od ?eightsa(g)'up Sex +atios (A $ales)'up 0linical Signs'up #ecrops bs.

#o. Evaluated 'ostweaning#o. ,ied or Sacrificed 2oribund0linical bservations

#ecrops bservationsod ?eight 0hangeb (g)*ood 0onsu$ption (Ab)'reputial SeparationSensor *unction2otor ctivit/earning and 2e$or2ean #o. ,as 'rior to 2ating#o. of 2ales that 2ated#o. of *ertile 2ales

8=1=.9

1=.7.1--971--

8=--

-817 g----8.B8=8=

811=.G

1=.G.--7G7=--

81--

-1F7----=.=8181

881B.F

1B.9.=--98BF--

88--

-1F7----8.F811F

1711.833

F.B331.G3

--7=571--

17--

-1G95-115----=.78=8

- #o noteworth findings. 3 2ild 332oderate 3332ar4ed

,unnettLs %est 5 - p6.7 55 - p6.1rus4al-?allis with ,unnLs procedure 3 - p6.7 33 - p6.1a - *ro$ birth to weaning.b - *ro$ weaning to $ating. *or controls! group $eans are shown. *or treated groups! percent differences fro$ controls are shown. Statistical

significance is based on actual data (not on the percent differences).(0ontinued)

109

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f y

2.6.=.1( eproductive ad &evelopmetal Toicity Study "o. ?2@1 ,0otiued

&aily &ose ,mg+-g @ ,0otrol =. = =@

*1*e$ales:

('ostweaning)

*8/itters:

#o. Evaluated 'ostweaning

#o. ,ied or Sacrificed 2oribund0linical bservations#ecrops bservations're$ating od-?eight 0hangea(g)


113/113

,unnettLs %est 5 - p6.7 55 - p6.1a - *ro$ weaning to $atingb - ,uring postweaning period. *or controls! group $eans are shown. *or treated groups! percent differences fro$ controls are shown. Statistical

significance is based on actual data (not on the percent differences). (0ontinued)

EC2'/E

2.6.=.1= Other Toicity Studies Test Article)0uritol Sodiu$

Species+Strai


&uratioof &osig

&oses,mg+-g


Study"um#er

Atigeicity

m4 safety step 4 sept02

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