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EXAMPLE OF DRUG DEVELOPMENT
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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
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TOXIC RANGE
THERAPEUTIC RANGE
SUB-THERAPEUTIC
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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
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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
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Chemical level
Starting in laboratory synthesis scale, then synthesis in semi-pilot scale
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Pharmaceutical development
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Pre-formulation
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Analytical and Bio-analytical methods
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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
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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