Exam 2 lecture 12 Flashcards
preclinical testing, research & development time range
1-3 years
avg: 18 mo
clinical research & development time range
2-10 years
avg: 5 yrs
NDA review time range
2mo-7yrs
avg:24 mo
phase 1
PK
dose-escalation study
safety (side effects)
in vivo biomarkers (initial response)
phase 2
initial antitumor efficacy
safety (Side effects)
in vivo biomarkers
PK
phase 3
clinical efficacy
safety & population PK
is phase 4 required?
no
purpose of preclinical studies
- establish a safety profile in ANIMALS prior to human use
- predict potential toxicity in humans
- provide rationale for studies in humans
implication of preclinical data
- provide basic pharmacology & toxicology info
- determine if the drug is sufficiently safe for human use
- provide data for continued use once clinical trials begin
- provide data for use in larger pt population or longer period
- predict potential toxicity in humans
- provide rationale for studies in humans
- determine side effects that are impractical or unethical to investigate in humans
animal commonly used to study HIV
monkey
animal commonly used to study CV
rabbits and dogs
animal commonly used to study toxicology & cancer
rates & mice
preclinical studies pharmacology profile
- MOA
- dose response relationship
- duration of action
- effects on major systems
- ADME
preclinical studies pharmacology screening
- to determine any pharmacologic action
- - CNS, CV system, autonomic nervous system, respiratory system, GI system, GU system
in vitro pharmacology study
- biochemical/pharmaceutical properties
- in vitro stability
- solbulity
- stability in cell culture/tissue culture
- plasma protein binding
- in vitro metabolism, cellular uptake, PK and PD
in vivo pharmacology study
- pharmacological effetcs
- effects on target site/system
- effects on other systems (animal model, readouts)
- data analysis
- implication in clinical trials
preclinical studies: toxicology
- aid in deciding if a drug should be tested in humans
- forewarn or predict potential hazards in humans
- define potential toxic or harmful effects of drugs in animals
types of toxicology testing
acute subchronic carcinogenicity reproduction & teratology mutagenicity
subchronic toxicology data implication
MOA pharmacologic activity target organs dose-response relationship sex difference
chronic toxicity testing protocol
duration: 3-12 months
species: 1 rodent & 1 non-rodent
treatment: multi-dose plus control
route: model human use
carcinogenicity testing protocol
duration: 2 years
species: 1 rodent & 1 non-rodent
treatment: multi-dose plus control
route: model human use
observation: cancerous growth
reproductive & teratology testing
- fertility & general reproductive performance
- teratology
- prenatal & postnatal study
toxicogenomic approaches
- link biological response to differential gene expression
- animal study (3 groups- vehicle control, low dose & high dose treatment)
- RNA microarray
disease research purposes:
- recognize subdivision of disease, leading to better testing model for testing of new therapy
- ID biomarker for preclinical & clinical trials
- ID disease mechanisms, leading to drug target ID & validation
- ID common links between diseases previously thought to be unrelated
acute modulation of target expresssion
transcription
translation
chronic modulation of target expression
- transgenic approach aka knock-in(overexpression of target gene)
- knock-out mice
- knock-down approaches
what is the role of a protein in biological effects?
increase activity» overexpression
decrease activity» inhibition (better model for drug action)
RNA interference (RNAi)
- easy to ID potent siRNA
- highly selective for target mRNA
- only sequence info required
- can be used both in vivo & in vitro
- potential for high throughput screening
- high efficacy
- difficult to deliver
- uncertain effects in vivo
- stabilizing in vivo
- selectivity in vivo to be determined
antibodies
- knowledge of target is required
- multiple targets frequent
- PK issues: ADME
- difficult to deliver
- slow & time consuming
- therapeutic potential
modulation of protein function
- antibodies
- dominant negative proteins
- aptamers
animal models that should represent chronic diseases
are difficult to model
e.g. COPD due to continuous exposure to smoke
animal models that should represent phenotypes
are difficult to define & measure
e.g. psychiatry (schizo, depression)
model organisms all to ID novel targets and pathways
drosophila
C. Elegans
zebrafish
mouse models
- transgenic
- knock-in/knock-out
- knock-down
zebrafish
- vertebrate whole animal in vivo model
- rapid embryogenesis & organogenesis
- easy development of visual & function screens
- large numbers of animals available for HTS
- cost-effective screening
- large sample size for statistical analysis
angiogenesis & zebrafish
- angiogenic vessels can be easily visualized in transparent zebrafish embryos
- many mammalian regulators of angiogenesis have been found (VEGF, ang-2, ang-1)
- gene knockdown in zebrafish generated phenotypes similar to mouse
easily targets organ systems in zebra fish
CNS, liver kidney, heart, GI, pancreas
