Lecture 13 - Drug development of a small molecule drug Flashcards
What occurred with elixir sulfanilamide?
- contained diethylene glycol, killing 107 people, mainly children
- the federal food, drug and cosmetic was passed by congress a year later
What occurred with sulfathiazole tablets?
- tainted with the sedative Phenobarbital, caused 300 deaths
- numerous control deficiencies in the plant and serious irregularities in the firms attempt to recall the drug
What occurred with thalidomide?
sleeping pill caused severe birth defect of arms and legs in Western Europe
What occurred regarding the thalidomide disaster (1960s)?
- 1954 first synthesized
- 1957 launched sleeping tablet ‘Contergan’ onto market
- Sold in over 40 countries under license
- US has not given licensing approval
- caused birth defects in 10,000- 20,000 babies
- 1961 withdrawn from most markets
Describe the process of drug development
- Basic research target selection
- Pre -clinical research
- Phase 1
- Phase 2
- Phase 3
- Regulatory review
What targets are involved in target selection?
- receptors
- enzymes
- transport proteins
What is involved in lead finding?
automated screens against libraries
What is involved in target selection?
Drug targets are, with few exceptions, functional proteins (e.g. receptors, enzymes, transport proteins)
There are usually identified from bio-science research
What is the process of lead finding?
When the biochemical target has been decided and the feasibility of the project has been assessed, the next step is to find the LEAD COMPOUNDS. The usual approach involves cloning the target protein - normally the human form, because the sequence variation among species is often associated with pharmacological differences, and it is essential to optimize for activity in humans. An assay system must then be developed, allowing functional activity of the target protein to be measured. This could be a cell-free enzyme assay, a membrane-binding assay or a cellular response assay.
What are the 3 steps in drug development?
Lead –> Preclinical development –> clinical development
What occurred in 1920 regarding animal toxicology and small molecules?
experiment to determine dose that would cause 50% death rate in mice and labelled it the median lethal dose (LD50)
What is the 3R initiative?
- reduce
- refine
- replace
aim to reduce animal use
Describe the effect of small molecules on rodents & non-rodents
For small molecules, the nonclinical safety studies need to be conducted in both a rodent model and a non-rodent model with the assurance that major human metabolites and the parent molecule are present and, therefore, qualified by at least one both of the nonclinical safety species
What is the default rodent used?
rat
What is the default non-rodent used?
beagle
What are the 3 dose groups?
- Low (no toxicology)
- Intermediate
- High (toxicology expected in target organ)
What is clinical pathology?
- haematology/clinical chemistry
- kidney and liver function
- coagulation
What is pathology?
- large organ toxicity
What is histopathology?
study of the structural manifestation of disease at the light microscopic level. It is largely a descriptive and interpretive science. The trained and experienced toxicologic pathologist must be able to distinguish normal variation and spontaneous disease processes from the changes resulting from the administration of a test article. Histopathology results are one of the most important parts of the nonclinical safety assessment process
What is the goal of toxicologic pathology?
In toxicologic pathology, the goal is to determine if the test article produces changes through a comparison of treated animals with control animal data (both concurrent and historical controls). It is important, therefore, that microscopic observations be recorded in a consistent, objective manner that readily allows tabulation (put in a table) and comparison of group effects. In this setting, the use of descriptive, rather than diagnostic terminology is preferred
What are the goals of non-clinical safety evaluations regarding toxicity?
- on/off target
- reversibility
What are the goals of non-clinical safety evaluations regarding toxicokinetics?
- relate toxicity to exposure
- max non-toxic dose/min affective dose
- dose selection for first in human
- identification of specific monitoring requirements
What is the purpose of preliminary toxicological testing?
to eliminate genotoxicity and to determine the maximum non-toxic dose of the drug (usually when given daily for 28 days, and tested in 2 species). As well as being checked regularly for weight loss and other gross changes, the animals treated are examined minutely postmortem as the end of the experiment to look for histological and biochemical evidence of tissue damage.
What does pharmacokinetic testing include?
includes studies on absorption, metabolism, distribution and elimination (ADME studies) in laboratory animals.
Chemical and pharmaceutical development to assess the feasibility of large-scale synthesis and purification, to assess the stability of the compound under various conditions and to develop a formulation suitable for clinical studies