EXAMPLE OF DRUG DEVELOPMENT

2

Objectives of preclinical testsPreclinical tests helps toEvaluate its toxicity

Assess its effectiveness

Propose a pharmaceutical form

Dose

Pla

sm

a C

on

cen

tratio

n

0 1 2 3 4 5 6 7 8 90

2

4

6

8

10

12

TOXIC RANGE

THERAPEUTIC RANGE

SUB-THERAPEUTIC

3

Objectives (2)Preclinical studies:Select appropriate models based on target and Mode of Action These studies can:

Provide nonclinical proof of principle regarding mechanism of action and efficacy

Guide schedule and dose escalation schemes Provide information for selection of test species Aid in start dose selection Selection of investigations biomarkers : The identification of pathways

involved in the mechanism of action is also essential for the selection of biomarkers of the biological activity which can be used clinically for the optimization of dosages and treatment regimens.

Justify pharmaceutical combinations Understand pharmacodynamic properties

4

IMIQUALINES Lead product

N

N N

NHCH3 N

N N

NHCH3

OCH3

EAPB0203 EAPB0503

N NH2

NN

CH3

CH3

Imiquimod

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Chemistry: A lead candidate was identified in Imiqualine family, a typical preclinical development program is

running with major efforts on:

Imiqualines

Chemical Development

Dérivés Méthoxylés

Dérivés Hydroxylés

Métabolites actifs

Pharmaceutical Formulation Liposomes

Mechanism of action

Analyse du Transcriptome

Effet inhibituer IKKB

Preclinical studies Modèles murins

6

Chemical level

Starting in laboratory synthesis scale, then synthesis in semi-pilot scale

7

Pharmaceutical development

8

Pre-formulation

9

Analytical and Bio-analytical methods

10

Non-GMP API

Analytical

Methods

Formulation

Bio-analytic

al Method

s

PK/Metaboli

sm

Dose-Range

Finding

Background, rational and justification for

dose selection

Preclinical Toxicity testing

Phase I: Clinical Protocol

11

Pre-IND document

Pre-IND meeting and recommendationsEstablish GMP manufacturing

process,lot release criteria,

stability, uniformity

Finalize preclinicalToxicologyprotocol(s)

Finalize Phase 1clinical Protocol(s),

ICFs

Background, rational and justification for

dose selection

Preclinical Toxicity testing

Phase I: Clinical Protocol

Written Pre-IND meeting request

PHARMACOLOGY TEST EXAMPLE OF ANTICANCER DRUG

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Cancer cell linesIn vitro studies performed in cell lines, cell-free systems

Often form the basis for screening and optimization during discoveryAnimal screening is too expensive for routine use

Cellular uptake and membrane transport MDR, MRP, etc Predictions of bioavailability and distribution In vitro drug metabolism: P450 isoenzyme inhibition or induction Effects on hERG channels (prolonged QT interval risk) Preliminary protein binding studies

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The NCI-60: Assessing drug effectiveness

NCI's In Vitro Cell Line Screening Project, better known as the NCI-60 analyzes the anti-cancer properties of a compound in human tumor samples from 60 different cell cultures, sometimes referred to as lines, representing leukemia, melanoma, and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney.

The NCI-60 project, which has been testing lines since 1990 in the Developmental Therapeutics Program of NCI's Division of Cancer Treatment and Diagnosis, screened 17,200 compounds in 2011, roughly evenly divided between natural and synthetic agents.

The most promising—the "hits"—move on to further testing.

Since 1990, more than 100,000 natural products have gone through the NCI screening process, driving the number of drugs in NCI's repository that have had some kind of screening process to over 400,000.

There is no cost to the researcher for NCI-60 screening.

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Comparison of variant counts across tumor types (NCI-60)

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Animal modelsEfficacy demonstrated in

disease specific animal models: Proof of therapeutic principle Groundwork for clinical

development planning Evaluation of therapeutic

index Toxicity versus efficacy

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Animal models (2)

Ideal Animal ModelValidity Selectivity Predictability Reproducibility

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Animal models for human prostate cancer

Spontaneous tumors:Idiopathic Carcinogen-

induced Transgenic/gene

knockout animals: p53, RB, etc

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Animal Pharmacokinetic models

Animal pharmacokinetics can guide dose and schedule selection ADME data can be generated in

parallel with clinical development Preliminary evaluation of

candidate biomarkers

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Cage à Métabolisme

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Murine Xenograft SitesSubcutaneous tumor (NCI method of choice) with IP drug administration:Intraperitoneal Intracranial Intrasplenic Renal subcapsule Site-specific (orthotopic)

organ inoculation

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Xenograft

Advantages

Many different human tumor cell lines transplantable

Wide representation of most human solid tumors

Allows for evaluation of therapeutic index

Good correlation with drug regimens active in human lung, colon, breast, and melanoma cancers

Several decades of experience

Disadvantages

Brain tumors difficult to model

Metastases rare

Survival not an ideal endpoint: death from bulk of tumor, not invasion

Shorter doubling times than original growth in human

Less necrosis, better blood supply

Difficult to maintain animals due to infection risks

Ability to mimic the human tumor microenvironment is limited

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Animal models (3)There is no perfect tumor model

How Predictive is the disease model in comparison to human disease ?????

CONTROLE INTRALUMINALE EXTRALUMINALE

ANGIOTENSINE II

Effet de l'endothélium sur la vasoconstriction induite par l'angiotensine ii dans une artère mésentérique de résistance