Pre Clinical Toxicology Flashcards
The regulatory agencies
UK - MHRA
EU - EMA
USA - FDA
Japan - PMDA
Drug Discovery Process
- Start with identification of suitable targets and the disease you want to treat
- High throughput screening and computer aided drug design (CADD) –> identifies target interactions and off target binding)
- Pre clinical phase: in vitro and in vivo testing. Analyse the toxicology, safety and dosing
- Phase I trials: healthy volunteers. Cross reference the data from the pre clinical trials
- Phase II trials: in diseased patients. Evaluate efficacy, dosing and side effects.
- Phase III: in 1000-3000 patients, to evaluate the long term effectiveness
- Phase IV: post market safety and efficacy e.g. FDA reviews, YC Scheme, carcinogenicity and genetic toxicity, aspects of drug metabolism
Typical pharmaceutical research and development pipeline
- high costs ($800 - 1000 million)
- 12-15 years for a new drug to move to discovery
- out of 10,000 compounds, only 1 compound is approved by FDA
Properties of a good drug candidate
- Good binding interactions
- Acceptable bioavailability
- Side effect profile
- High receptor selectivity and affinity
- Active in animal models
- Novel
- Good pharmaceutics
- Good pharmacokinetics
How is pre-clinical drug discovery a balancing act?
- target interaction and off target interaction
- desired effect without having unwanted side effects
- sufficient exposure to the target whilst ensuring there is a balance of metabolism, clearance and absorption
Why do we do Toxicology?
· Effects of substances on human health of voluntary exposures (pharmaceuticals)
· Safety in the workplace and in transport (labelling, msds)
· Effects of substances on human health of involuntary exposures (food activities and contaminants)
· Investigation of causes of unusual levels of disease
Environmental impact of use and production of substances
Objective of Toxicology Studies
to assess and subsequently manage potential hazards to man, to other animals and to the environment
What is the aim of toxicology studies? i.e. what outcome do they want from it
□ Toxicology studies should permit a quantitative determination of the potential for a chemical to produce local and/ or systemic effects
□ These studies should allow a determination of factors that may influence the nature, severity and possible reversibility of effects
What do we need a detailed knowledge of in order to achieve the objective?
- find out maximum tolerated dose and the no observed adverse event limit
- knowledge of cumulative toxicity
- knowledge of its mutagenic, carcinogenic and teratogenic potential
What conditions are toxicology studies carried out in?
A strictly regulated environment:
- Frequent and random external inspections
- Operate under GLP guidelines
- Licence to carry out trials
- Declare what they are doing and have approval from the home office
- Ethical reviews
- Tightly regulated
- Toxicology report itself is assessed
Is data obtained from animal models useful?
- chemicals that cause toxicity in animals can be extrapolated to humans BUT no direct correlations
What is the pre-clincial design?
- conducted in animals
- tests conducted prior to commmencement of human trials
Purpose of 3Rs
principles that are followed in animal studies to ensure they are conducted in a regulated environment with the most humane regime to obtain good quality information
What are the 3Rs
- replacement
- reduction
- refinement (methods that minimise pain, suffering and distress of animals_
What is the role of pre clinical testing?
- required to support clinical development
- provides information concerning risk to patients
- prevent the development of unsafe drugs
e.g. teratogenic effects of thalidomide
