drug discovery
TRANSCRIPT
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)
• 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
marketingpost registrationmonitoring
lessons&development
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 + receptorBINDING
+ transductionsystem (secondmessenger; enzyme)
BIOCHEMICAL TESTING
functionalwhole orpart organs
ISOLATED TISSUE EXPERIMENTS
Anaesthetised or conscious animals
WHOLE ANIMAL EXPERIMENTS
• 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 of efficacy
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
R R R
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.
• 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.
Safety & toxicity in animals
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
sequential
cross-over
others:-- matched pairs; combinations; ++
AB
A
A
B
BBA
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
0
Unit sales
Time
serious side effectsadverse reactions
wonder drugno side effects
not alwayseffective
appreciate where bestused and risks
balanced view ofadvantages &problems
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