Lecture 5: Preclinical studies Flashcards
Pre-clinical ‘proof of principle’
- lead optimisation (dozens of compounds)
- Candidate seeking
- preclinical development
preclinical drug development
Vital to gather as much safety and efficacy data at this stage to support future regulatory submissions
Aims of preclinical drug development
Assess potential therapeutic effects of drug candidate in relevant organisms
Gather sufficient preclinical data on the drug to evaluate safety of drug candidate for human use
To determine if drug candidate has potential to ever be developed as a pharmaceutical for human use
- not just to do with safety and efficacy, but also manufacturing etc
Who does preclinical drug development?
Big Pharmaceutical companies
* Traditionally done in-house
* Increasingly being out-sourced to preclinical contract research organisations (CRO’s)
Larger biotechnology organisations
* Some done in-house
* Mainly out-sourced
Smaller biotechnology organisations and Universities
* Little done in-house
* Primarily out-sourced
Identifying a lead candidate series
- Preclinical profiling begins when a lead compound(s) has been discovered.
- Assessing efficacy in early animal models
- Identifying signs of potential off-target or toxic effects.
- Early PK profiling (to compare with in vivo efficacy)
4 Primary areas of preclinical testing
Efficacy testing
- How does the drug work?
- How effective is the drug?
- Cell based assays
- Animal models of human disease
ADME
- What does the body do to the drug?
- What is the most effective way to deliver it?
- Relevant animal models
Toxicology
- Is the drug safe?
- Are there any contraindications?
- Primarily animal testing
- In vitro and in silico approaches
Pharmaceutics
- Is drug manufacture feasible and reliable?
- Physicochemical properties
- Formulation studies
Efficacy testing
How does the drug work?
How effective is the drug?
Cell based assays
Animal models of human disease
“Proof of concept” studies in animal models of disease
In vitro tests
In vivo models (typically rodents)
what does in vitro (?) testing look out for
- binding affinity or potency and efficacy
- high selectivity
- functional cellular assays:
(- enzyme inhibition - inflammatory mediators
- neuronal cell death )
in vivo testing 4 outcome measures
typically performed on rodents
- make sure you measure key outcomes relevant to disease pathology
- make sure its testing in a relevant animal model
- determine if a beneficial effect is observed
- is effect seen at a dose realistic for humans?
ADME
Pharmacokinetics (pk) = sum of ADME process = what happens to the drug inside the body
Adsorption: movement of drug into bloodstream
Distribution: tissue distribution from site of absorption
Metabolism: biotransformation into more polar forms (hydrolysis, conjugation, oxidation)
Excretion: excretion of active drug and metabolites
most ADME usually performed by LC-MS (liquid chromatography mass spectrometry)
tissue distribution
at end of trial kill animal, collect tissue and look at tissue distribution
PK/PD relationship
relationship between pharmacokinetics and pharmacodynamics
= effect over time
5 types of toxicity testing
- Acute toxicity
- Repeat-dose toxicity
- Carcinogenicity
- Genetic Toxicity
- Reproductive toxicity
aim of toxicity testing
- identify safe starting dose and subsequent dose escalation scheme in humans
- identify potential organ system toxicities and whether such toxicities are reversible
- identify safety parameters for clinical monitoring
Acute toxicity studies: design and endpoints
Design:
1. at least 2 species (both sexes)
2. 2 routes of administration (Iv and intended route)
3. emphasis on signs of toxicity and mode of death rather than LD50
4. 3-5 rodents per sex per dose
What to look out for:
1. gross signs of toxicity (death etc)
2. changes in behaviours (hyperactivity, aggression)
3. changes in fur, skin, mucous membranes
4. observing tremors, salivation, sleep etc
5. weight monitored
