drug discovery and clinical trials Flashcards
drug discovery initial identification
published research disease knowledge pharmaceutical analysis generating hypotheses traditional or herbal luck metabolites of existing drugs
cellular drug targets
g protein coupled receptor
drugs as selective ligand
cellular drug targets
ion channels
challenging due to pore forming homology
cellular drug targets
transport proteins and enzymes
protein kinases, targets for oncology
genetic associations
GWAS sequencing of whole genomes allows for identification of subgroups requirements for new personalised medicines
high throughput screening target validation
large no. modulators against drug candidate to rapidly exclude those with poor response
bioinformatics
analyse data sets to show targets and understand disease processes to identify drug targets
Pre
pharmacodynamics PD
what drug does to the body
Pre
pharmacokinetics PK
what body does to the drug
Pre
basics of PRECLINICAL study
animal models no humans PK PD safety and toxicological investigations pharmaceutical development-large scale feasibility
Pre
pharmacodynamics research
site/mechanism of action
influence of age sex and other factors
dose-response
Pre
pharmacokinetics research
absorption- rate and bioavailability
distribution in tissues
metabolisms - accumulation and interactions
excretion- clearance and organ
Pre
safety and toxicological
adverse effects non toxic dose therapeutic range post mortem for tissue damage intra and inter species variability
Pre
pharmaceutical development
formation and administration
large scale synthesis/purification feasibility
compound stability under different conditions
when can Pre go to clinical
once thorough and comprehensive preclinical satisfied a regulatory body for safety and efficacy can move on to human testing
basics CLINICAL TRIALS
human volunteers
expose more people collect more data
needs authorising by medicines and healthcare produce regulatory agency MHRA
good clinical practice
phase 1 clinical trials
initial human administration
estimate safety and dose range
small n of health volunteers
use exhaustive pre clinical data to minimise risk
specialist units and trained investigators for consequences
phase 1 clinical trial administration
slow infusion
SAD-single ascending dose, if no adverse effects increase dose in a new group until side effects or PK safety
MAD
phase 1 clinical trial Pharmacokinetics PK
measure at freq. intervals for conc vs time
absorption, distribution, metabolism, excretion
monitor any variance from pre clinical animal models
phase 1 clinical trial pharmacodynamics PD
consider mechanism of action, specificity and immune targets
body system disturbances
high potency
phase 1 clinical trials drug dose
MABEL- minimum anticipated biological effect level(minimum dose to cause biological effect in human)
NOAEL- no observed adverse effect level(highest does no adverse effect)
p1 clinical trial volunteers and objectives
small number less than 20 or 30 of healthy volunteers with no other medication with valid informed consent (or cancer patients) determine MTD (max tolerated dose) and MEC (minimum effective conc)
p1 ADME
absorption into systemic circulation
distribution of drug into tissues
metabolism and or metabolites
excretion of drug from body
p2a basics
same as p1 but larger n 50-500
can look at differences in age
appropriate dosage in patients
p2b basics
therapeutic range assessed for efficacy
pivotal trials-evidence for drug marketing approval
once shown effective against disease or condition can go to p3
p3 basics
therapeutic confirmation using large n and RCT
large and long term assessment on safety
p3a
before drug application submission
use on patient pop
info on labelling
modelling for drug drug interactions and differences in subgroups
p3b
after application but before approval/marketing
supplements earlier trials
increased patient exposure
p4
post registration and licensing
2000-10000
comparison against other drugs
continued pharmaco-economic evaluation
RCT gold standard basics
intervention vs control
follow up and measure outcomes at time points
single or double blinded
randomisation
PICO
population
intervention
control
outcome
RCT problems
noncompliance missing outcomes(loss follow up)
NNT-number needed to treat
average no. patients receive treatment before ones positive outcome - ideally close to 1
NNH-number needed to harm
chance of experiencing harm because of intervention
should be large
types of RCT design
superiority- show more effective
equivalence - show same benefit, clinically unimportant difference
non inferiority - effect not weaker than current
RCT advantages
comparable groups
valid stat tests
closely matched groups
gold standard
RCT disadvantaged
cost and time
generalisability issues
recruitment
complex administration
