Intro to drug discovery

Question 1

Routes of drug discovery

Answer 1

Can be biological or chemical

Biological starts with target identification and validation. assays will then be developed for the selected target and HTS screening assays are then conducted.

Chemical starts with compound libraries and HTS is then conducted.

Once HTS is done, primary hits are chosen for secondary assays, then lead identification and lead optimisation. This will give a drug candidate.

Question 2

When are efficacy, PK and toxicology studied

Answer 2

Efficacy studied from lead discovery all the way through preclinical development.

PK studied from lead optimisation onwards. lead optimisation sees HTS of PK parameters. will be used to refine the PK and identify a first in human dose (in preclinical development).

Preclinical toxicology studied during preclinical development.

Question 3

Principle assays of early drug discovery

Answer 3

Target validation - gentic, cellular, and in vivo models to identify/validate the target

compound screening: HTS and library screens. reiterative directed compound synthesis to improve the properties.

secondary assays are in vitro and ex vivo to identify mechanistic and selectivity characteristics.

in vivo analysis applies the compounds to disease efficacy models and to identify early toxicology. here a candidate is chosen for preclinical toxicology.

Question 4

Phase 1 clinical trials

Answer 4

identify the safety and tolerability of the drugs in a small number of healthy volunteers.

looks at PK (Cmax, Tmax, AUC, Cl, and T1/2) and PD.

test immunogenicity, adverse effects, vital signs, biochemical and haematological biomarkers, ECG, and additional drug-specific concerns.

single ascending dose studies conducted to identify a MTD once intolerable side effects appear.

Then multiple ascending doses studies can be conducted got be used in phase2/3 trials.

Question 5

Phase 2 clinical trials

Answer 5

100-300 patients.

determine pharmacological effect in humans + further toxicology.

Phase 2A finds the therapeutic dose

Phase 2B finds the efficacy of drug in small population

Question 6

Phase 3 clinical trials

Answer 6

100s-1000s of patients - usually randomised and in multiple centres.

aims to determine if the drug has the desired effect in relevant patient populations compared to placebo or current treatments. Further toxicology too.

at the end of phase 3, a submission for New Drug Application for Marketing authorisation will be done.

Question 7

What is phase 4 trials

Answer 7

post marketing surveillance to monitor drug in wider population for rarer adverse effects