Drug Discovery 5 Flashcards
what is the aim especially early on in the drug discovery process?
avoid DMPK failure during development
predict safe and effective dose regimens in humans
what 6 key areas does Pharma seek to optimise early on in the discovery process ?
bioavailability controlling CNS exposure metabolite identification clearance avoid drug-drug interactions
what does a drug have to be to be able to cross the BBB for CNS exposure but what can cause problems ?
it has to be lipophilic because the capillaries are continuous in the brain to prevent the entry of toxins
P-glycoproteins are the brains defence mechanism against lipophilic drugs- these proteins can pump the drug back into the lumen
how can polar drugs enter into the brain ?
they can only enter if there is a specific carrier for them
e.g L-DOPA is an amino acid which can enter the brain via carrier proteins
give an example where a drug couldnt cross the BBB was an advantage…
atenolol cannot cross the BBB like propranolol which was good because propranolol caused sleep disturbanes
how can P-glycoprotein susceptibility be determined?
using MDCK-MDR1 monolayers
these are cells are a standard tool to determine if a drug is a candidate for P- glycoprotein
like Caco-2 cells they are polarised so they have apical and basolateral surfaces
they carry Pglycoproteins recombinantly
the drug is applied to the top chamber at the apical surface and then the amount of drug which enters the bottom chamber can be determined and then this process of diffusion is carried out in the opposite direction-if the drug is P-glycoprotein substrate then it will be pumped back into the top chamber
useful at looking at bioavailabilty as well
what should the ratio efflux produce by comparing apical-to-basolateral with basolateral-to-apical diffusion be ?
1
if it isnt then it siggests the role of P-glycoprotein - this can be assessed by inhibiting P-glycoprotein with cyclosporin
why is it useful to understand the mechanism and sites of action of a drugs metabolism ?
may help identify active metabolites - complicate the pharmacokinetic-pharmacodynamic relationship
may help avoid risk of reactive and toxic metabolites -
what methods can be used to identify safety issues ?
in silico method combined with several liver microsome assays - this only removes the really obviously dangerous compounds
what is an active metabolite and what are the issues surrounding them ?
active metabolites are compounds which despite having been metabolised, end up being more active than parent drug - this can complicate dosing and can unbalance the relationship between pharmacokinetics and pharmacodynamics
what can be used to make predictions about active metabolites ?
knowing the structure- activity relationship of the drug
knowing the pharmacophore of the drug
these coupled with likely metabolic products
what is an extreme case of active metabolites ?
when candidate compound is inactive and is converted to an active drug in the body- this can be useful in improving absorption or distribution
e.g L-DOPA
if metabolites are reactive what can this cause ?
lead onto toxicity, immunogenic responses, mutations and tumour formation
for optimal clearance what does a drug need ?
low clearance and a suitable half life - cant be tested in humans
can only be tested in humans once it has reached clinical trials
what are the 2 stages of optimising clearance ?
stage 1 = identify the key elimination processes that control clearance
stage 2 = optimise these processes using animal and in vitro human models
what are example of elimination process which can be controlled?
metabolic= block enzymes or modify moeity renal= block OATs or increase lipophilicity biliary= difficult
how can one drug affect the pharmacokinetic properties of another drug ?
INHIIBITING A CYP= screen with assays
INDUCING A CYP= screen using hepatocytes or HEPA-RG cells
INHIBITING AN UPTAKE/EFFLUX TRANSPORTER= screen for inhibition of OAT, P-glyP
what processes occur during pre-clinical testing ?
- an optimised lead compound is chosen as the “pre-clinical development compound” and another is chosen as a back up
- legal processes start to maximise human safety
- large amounts of the lead compound are produced at a quality for human consumption - often means new synthetic pathways have to be developed
- multiple species toxicity tests carried out
what happens in phase 1 of clinical testing ?
healthy individuals are used to look at clinical safety in humans - only a few used
look at pharmacokinetic properties and safety of the drug to determine an appropriate route of admin and safe doses
only a few months long
what happens in phase 2 clinical trials ?
info from phase 1 is used to aid design of phase 2 studies and these are carried out in a few patient subjects
provide info about clinical efficacy and help to further determine safety
last from a few months to 1-2 years
what happens in phase 3 clinical trials ?
these are used to establish effectiveness and safety in a varied and large population of patients
several hundred to thousands of patients
lasts for several years
are there any trials after the drug is marketed ?
yes
phase 4
purpose of them is to provide additional data on drug safety and clincial benefit
last for entire duration of drugs life
important for detecting rare and unpredictable adverse drug effects
what does drug discovery require ?
appreciation of molecular structure of ligand and target
understanding of the principles of how molecules interact
