Transcript Drug development - British Pharmacological Society

Drug discovery and development
• Ian Hughes, [email protected]
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)
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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)
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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
lessons
&
development
post registration
monitoring
regulatory process
marketing
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
system (second
BINDING
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)
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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
sequential
crossover
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others:-- matched pairs; combinations; ++
The Regulatory process
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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
wonder drug
no side effects
not always
effective
balanced view of
advantages &
problems
appreciate where best
used and risks
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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?
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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