Drug Development Flashcards
What is Thalidomide and what did it’s discovery in 1962 cause?
> Sleeping tablet
> Caused severe birth defect in arms and legs; is the biggest reason why drugs needed more safety checks.
What are the 3 steps to creating a drug?
Basic research, Pre-clinical research, Clinical research
What are the 3 stages of clinical trials and what occurs at each stage?
1) Phase I: healthy humans
2) Phase II: On patients to check doses (many drugs fail here)
3) Phase III: costs the most, finds proof that the drug works and should be approved.
After we have found a drug what 3 steps do we take?
1) Lead selection
2)Pre-clinical Development
3) Clinical Development
In the 1920s what technique was used to test for toxicity of a drug?
LD50 = tested dose of a drug until 50% of animals died.
What is Toxicokinetics and why is it done?
> Increase the dose of a drug and see how long it takes to clear
> Tests to see linear toxicity effects.
What are the 5 aims of preclinical development?
1) Provide a safety margin
2)Find the dose/ conc to start human trials with.
3)Find the max dose/conc to be dosed to humans.
4) Define the target organs and the rescue treatments
5) Obtain regulatory approval.
What are the 5 goals of non-clinical safety evaluations?
1)Toxicity
2)Toxicokinetics
>How long drug takes to clear
3)Max non-toxic dose / Min affective dose
4)Dose selection for Fist in Human
5)Identification of specific monitoring requirements
Describe tests used to explore drug safety during lead selection for small molecule drugs by 1) Animal toxicology 2) General toxicology
1)Animal toxicology
>LD50 (increase dose until 50% of animals die)
>3R: Reduce, refine, replace (keeps animals alive)
>Test drug on Rodent and non-rodent
>Test 3 doses (low dose, intermediate and high)
2)General toxicology
>Clinical pathology (in lab) tests kidney and liver function (where drugs are metabolized).
>Pathology (after animals died) checks if the drug was toxic to the large organs.
What are 3 targets for drugs?
Receptors, enzymes, transport proteins.
What is lead finding and why is it useful?
Automated screens against libraries to build model to mimic the target, this allows us to quickly screen this model against millions of proteins to see if we have a complimentary drug.
Describe the 4 stages of development of a new drug
1)Phase I
>Is it safe?
>How well is it tolerated?
>What are the pharmacokinetic properties?
2)Phase II
>How much should be given to be effective?
>How well does the treatment work?
3)Phase III (Expensive)
>1000+ patients
Multi-nation al so is hard to organize
>Apply for marketing once granted.
4)Phase IV
>Post marketing surveillance
>Detect rare or long-term adverse effects
>Many drugs are removed after put on the market.
What are 4 differences during animal toxicity testing with biopharmaceuticals instead of small molecules?
1) Injecting a human protein causes an immune response in the animal:
>accelerated clearance (drug disappears quicker)
>prolongation of exposure (drug stays longer)
>neutralize the pharmacological activity (drug neutralized)
2)Need to pick a specific animal model which will respond to a human protein.
3)Animals will have a different reaction to the toxicity of a human protein than humans will.
4)On-target toxicity (target organ) is very high and is not always linearly linked to the concentration of the drug.
What is more common with Biopharmaceuticals: off-target or on-target toxicity?
On-target is higher, meaning the target organ is effected by toxicity more than off-target organs.
What are the 3 type of drug structures and their properties?
1)Small molecule
>Low molecular weight
>Chemically synthesised
>Well defined structure
2)Biological molecule
>High molecular weight
>Derived from living organisms.
>Large and complex structure
3) Monoclonal antibody
>High molecular weight
>Derived from living organisms.
>Most complex structure
