Drug discovery and development

• Ian Hughes, i.e.hughes@leeds.ac.uk

Objectives of next 5 lectures: you will:
• be aware of why/how new drugs are discovered
• know the processes involved in drug discovery and
development
• see where pharmacologists/bioscientists may contribute
• know about the difficulties and dangers inherent in the
drug development process.
 What is a drug?

• Any chemical compound - sugar ???

• Anything which produces a change in
the body - an axe ???
• Define by characteristics:
1. use or potential use in diagnosis or
treatment of disease
2. selective in their actions
 What costs what in Leeds? (GPs; 98/99)

• Omeprazole (anti-gastric acid) £3.5m

• Simvastatin (cholesterol lowering) £2.4m
• Beclomethasone (asthma) £1.8m
• Fluoxetine (antidepressant) £1.5m
• Lansoprazole (anti-gastric acid) £1.4m
• Ranitidine (anti-gastric acid) £1.3m
• Paroxetine (antidepressant) £1.2m
• TOP 7 TOTAL >£13m
• Total GP drugs for Leeds >£67m
 Why are new drugs needed?
• unmet medical need; new diseases (BSE; AIDS,
Alzheimer’s; obesity); low efficacy (dementia, cancer); side
effects (antidepressants, antipsychotics)
• downstream health costs; (Alzheimer’s; spinal injury)
• cost of therapy; (Viagra, Interleukins)
• costs to individual/country; (depression)
• sustain industrial activity; pharmaceutical industry
employs thousands and makes a massive contribution to
overseas earnings); patent expiry
 The changed context of drug
discovery and development

The 1800s: natural sources; limited possibilities;

prepared by individuals; small scale; not
purified, standardised or tested; limited
administration; no controls; no idea of
mechanisms.
The 1990s: synthetic source; unlimited
possibilities; prepared by companies; massive
scale; highly purified, standardised and tested;
world-wide administration; tight legislative
control; mechanisms partly understood.
 Sources of drugs
Animal insulin (pig, cow)
growth hormone (man) (Creutzfeldt-Jakob)
Plant digitalis (digitalis purpurea - foxglove)
morphine (papaver somniferum)
Inorganic arsenic mercury
lithium
Synthetic chemical (propranolol)
biological (penicillin)
biotechnology (human insulin)
 Drug discovery/development process

discovery; refinement; chemical & biological

characterisation

safety & toxicity in animals; formulation development

volunteer studies; patient studies regulatory process

lessons marketing
& post registration
development monitoring

Discovery=find new active structure : Development=convert it to a useful drug

 Approaches to drug discovery
• Historical; cinchona (quinine) & willow barks (aspirin); chinese medicine
currently.
• Study disease process; breast cancer (tamoxifen); Parkinson’s
disease (L-dopa)
• Study biochem/physiological pathway; renin/angiotensin
• Develop SAR to natural compound; beta-adrenoceptors
(propranolol), H2-receptors (cimetidine)
• Design to fit known structurally identified biological
site; angiotensin-converting enzyme inhibitors
• By chance (serendipidy); random screening (HTS);
penicillin; dimenhydramate; pethidine
• Genomics; identification of receptors; gene therapy; recombinant materials;
DRIVER IS UNMET MEDICAL NEED IN A VIABLE MARKET
 Refinement of compounds

• Can it be improved? selectivity; duration; route of

administration; stability, isomers, ease of
preparation.
• Can it be patented? costs £250m; takes 8-14 years;
high risk business.

USE iterative approach

 Levels of testing

DRUG + receptor
+ transduction
BINDING system (second
functional
messenger; enzyme)
whole or
BIOCHEMICAL TESTING part organs
ISOLATED TISSUE EXPERIMENTS

Anaesthetised or
conscious animals
WHOLE ANIMAL EXPERIMENTS
 Animal models of efficacy
• Existing normal behaviours/effects (anaesthesia; contraception;
paralysis)
• Create behaviours (fat rats; hypertensive rats; anxious rats;
epileptic rats)
• Find unrelated behaviour affected by existing drugs (Straub tail
for narcotic analgesics; learned helplessness for antidepressants)
How predictive is the model?
exact replica = 100% predictor
mechanism same = good predictor
mechanisms different = poor predictor
 Animal models

• predictive for efficacy AND toxicity?

• expensive; time consuming; variable; uncertain; troublesome;
ethical questions; skilled workers
• legislative control
Animal (Scientific Procedures) Act (1986)
• PERSONAL LICENCE - competent, trained, procedures specified
• PROJECT LICENCE - allows a personal licence holder to carry out
specified procedures for a specified project that cannot be done
without animals and where severity justifies likely gain.

• GET INTO MAN EARLY

RRR
 Reducing animal usage
• About 2.6m animals/y used in procedures in UK (11.6m in Europe)
• Likely to increase; more research, more targets, genetic capability

•3Rs -- 3Rs -- 3Rs

• REPLACEMENT: use non-animal tests if possible (cheaper,
less trouble, less variable but not possible for everything at this
time)
• REDUCTION: get the statistics right, don’t replicate work
unnecessarily, don’t overbreed
• REFINEMENT: reduce suffering and severity of procedure, pay
attention to housing, stress, husbandry and rich environments,
proper analgesia and pre- and post- operative care
 Chemical and biological
characterisation
• CHEMICAL; structure, synthesis, purity, isomers,
pKa, stability, solubility, salts, assay
• BIOLOGICAL; acute pharmacological profile -
LD50, ED50, binding data for many receptors, dose-
effect relationships, open field tests, particular
tests for different activities (e.g. CVS, CNS, GI tract)

Both positive and negative information is useful.

 Safety & toxicity in animals
• Acute toxicity profile
• Chronic toxicity profile
-- 14 day toxicity test in one rodent and one non-rodent species
before use in man.
-- 3 month study read out at 28 days
-- longer studies (12 & 24 month)
Three dose levels (below, about, well above human dose).
It is insufficient to to use doses which are not toxic; the doses
producing toxic effects and the nature of these effects MUST
be established.
 Formulation studies
• DRUG +
Additive: filler, lubricant, coating, stabiliser, colour,
binder, disintegrator
Dosage form: capsule, tablet, injection, other?
Manipulate duration/profile: e.g. sustained release

Bioequivalence
Bioavailability
Ease of use
 Clinical testing
• {Phase 0 (non-clinical)}
• Phase 1 (volunteers)
• Phase 2 (patients)
• Phase 3 (large scale multi-centre)
• Phase 4 (post registration monitoring)

phases can also be defined by the information you are

trying to get out of the testing
 Volunteer studies (phase I trials)
• pharmacologists & employees (15-30 in number)
• ethical approval
• healthy
• informed consent
• full rescussitation + medical backup
• monitor
• single and repeat doses
• increase dose levels
 Volunteer studies (phase I trials)
OBJECTIVES
• metabolic and excretory pathways (impinges on
toxicity testing in animals)
• variability between individuals; effect of route;
bioavailability
• tolerated dose range
• indication of therapeutic effects
• indication of side effects
 Patient studies (phase 2 trials)

• 150-350 ill people; informed consent

• needs licence
• maximum monitoring; full rescussitation
• often patients where other treatment failed
• OBJECTIVES:
indication for use; type of patient; severity of disease;
dose range, schedule and increment;
pharmacokinetic studies in ill people;
nature of side effects and severity;
effects in special groups.
 Patient studies (phase 3 trials)

• 1500-3500 ill patients

• multicentre?
• more certain data for the objectives of phase 2
studies
• interactions between drugs start to become
measurable in the larger population
• sub-groups start to be established
• special features and problems show up
 Clinical trials
Drug action depends on:
• pharmacodynamics
• pharmacokinetics and dose regimen
• drug interactions
• receptor sensitivity of patient
• mood/personality of patient & doctor
• patients expectations and past experience
• social environment of patient
• clinical state of patient
Clinical trial controls these variables and examines action of drug in
defined set of circumstances
 Clinical trials
controlled or uncontrolled
open or blind
parallel
A
B
sequential
A B
cross- A A
over B B
others:-- matched pairs; combinations; ++
 The Regulatory process
• differs from country to country
• demands safety and quality of product
• encourages efficacy and need for product
• grants clinical trials certificate if volunteer and animal data OK
• approves protocols and examines data
• 50-400 volumes (30,000-150,000 pages)
• original data available
• two way process; authority and company trying to produce a safe
effective product
• release for a specific purpose and use
 Marketing
• getting the product right (packaging;
formulation)
• right therapeutic slot
• information on new drug
• information for honest comparison
• reporting problems
• reporting new indications
• therapeutic trends
 Classic sales curve
Unit sales
serious side effects
adverse reactions
balanced view of
advantages &
wonder drug
not always problems
no side effects
effective

appreciate where best

used and risks

0 Time
 Post-registration monitoring
• YELLOW CARD SYSTEM: voluntary reporting of
adverse effects by GP to Committee on Safety of
Medicines; easy; effective?
• INTENSIVE MONITORING OF DEFINED GROUP:
first 10,000; administrative nightmare as patients
move/die; costly; time-consuming.
• RESTRICTED RELEASE: only available to small
group of GPs; monitor their patients; elitist
• MONITOR INCIDENCE OF DISEASE PROBLEM:
difficult to identify cause of change.
 Lessons and development

• refine parts of treatment giving problems (dose interval?

side effects? effective? niche market?)
• extend usage
eg. PROPRANOLOL (beta adrenoceptor blocker)
antidysrhythmic >>> antianginal >>> antihypertensive >>>
relieve hyperthyroid symptoms >>> antihypertensive
with diuretic >>> prolonged release formulation

precipitate asthma attack > beta1 selective - ATENOLOL

 The future?
• 3rd world diseases?
• orphan drugs with few users?
• improve safety and efficacy records
• reduce animal utilisation (cell lines; early human
volunteers, )
• new diseases (AIDS; Alzheimer’s; CJ disease;human
BSE variant; obesity; cancer)
• new biology - (clone human receptors; disease
model by gene changes)
• patent times and increasing cost
 Me-too drugs
Similar to drugs already on market
• parallel co-incident development
• not identical - differences emerge with time
• allergy to one only
• unsuspected side effect causes discontinuation
• particular indication in sub-group of patients
• sometimes too many