The translational journey of a medicine L5

Question 1

why drug discovery / development

Answer 1

• medicines save and transform lives
• pharmacology
  -small molecule drug discovery

Question 2

dosage definition

Answer 2

measured and specific amount of a medicine, with number, and frequency of doses over a specified period of time or prescribed intervals.

Question 3

efficacy in pharmacology

Answer 3

maximum functional effect that a drug – receptor complex can produce

Question 4

potency definition

Answer 4

-amount of a drug that is needed to produce a given effect
-e.g. EC50 is the concentration of drug that causes 50% of maximum effect
determined by affinity of drug for receptor and number of receptors available

Question 5

efficacy in trials - efficacy vs effectiveness

Answer 5

• Efficacy - the ability of a medicine to provide a beneficial effect when studied in aclinical trial - a positivebenefit/riskratio
• Effectivenesshow well a treatment works in the real world medical practice
  opposed to efficacy, only inclinical trials

Question 6

Pharmacodynamics

Answer 6

Primary:
Determine how the intervention causes the body to react (efficacy)
- in vivoand/orin vitro.

Secondary:
Determine how the intervention acts on other aspects of the body (i.e. not the target). Not always needed; published literature enough information.

Safety:
identify undesirable effects on key physiological functions within the therapeutic dose range and higher.

Usual studies CNS, and cardiovascular and respiratory functions.

Question 7

pharmacokinetics

Answer 7

Pharmacokinetic studiesaim to address:
ADME: A (absorption), D (distribution), M (metabolism), E (excretion)

Toxicokinetics
how much of the intervention is in the body and where/when undesirable effects happen

Question 8

Toxicology

Answer 8

Initially conducted in rodents (mice or rats), followed by studies in a larger animal species (for example dogs)
The objective is to establish thetox profile
themaximum tolerated dose, and the non-observed adverse effect level (NOAEL).
Identify target organ(s) oftoxicity
Establish doses for first-in-human dosing and clinical trials

Establish the toxicity profile when administered repeatedly for a given period of time
and Identify target organ(s) oftoxicity
Reversibility of adverse effects

The standard duration is:
Sub-chronic: 7, 14 and 28 days and 3 months
Chronic: 6, 9 and 12 months

Question 9

small molecule drug discovery

Answer 9

Compound libraries “screened” using models ( cellular, tissue, or even whole animal) to discover a “HIT”
a chemical or mixture with recognisable activity

Lead identification/ development stage :
When Hit discovered, analog synthesis to improve activity in the screen
Develop a structure–activity relationship.

Lead compound optimisation
Leads identified with sufficient pharmacological activity, preliminary animal toxicology and pharmacokinetic studies and pharmaceutical characteristics understanding

Clinical candidate - studies required by regulatory authorities to proceed to clinical testing and to the market.

Most of the time, the initial clinical candidate fails due to poor pharmacokinetics, safety, or efficacy.

Question 9

NOAEL