Drug Discovery

Drug discovery and development
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,
Alzheimers; obesity); low efficacy (dementia, cancer); side effects (antidepressants, antipsychotics)
downstream health costs; (Alzheimers; 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 Plant
insulin (pig, cow) growth hormone (man) (Creutzfeldt-Jakob) digitalis (digitalis purpurea - foxglove) morphine (papaver somniferum) arsenic mercury lithium chemical (propranolol) biological (penicillin) biotechnology (human insulin)
Inorganic Synthetic
Drug discovery/development process

discovery; refinement; chemical & biological characterisation safety & toxicity in animals; formulation development
volunteer studies; patient studies lessons & development
regulatory process marketing
post registration monitoring
Discovery=find new active structure : Development=convert it to a useful drug
Approaches to drug discovery

Historical; cinchona
currently. disease (L-dopa) (quinine) & willow barks (aspirin); chinese medicine
Study disease process; breast cancer (tamoxifen); Parkinsons 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
BINDING
+ transduction system (second messenger; enzyme)
BIOCHEMICAL TESTING
functional whole or part 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
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) unnecessarily, dont overbreed
REDUCTION: get the statistics right, dont replicate work 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 sequential crossover
A B A A B B A 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 wonder drug no side effects not always effective balanced view of advantages & problems
appreciate where best used and risks
Time
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.
Post-registration monitoring
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; Alzheimers; 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

Drug Discovery

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Drug discovery and development

What costs what in Leeds? (GPs; 98/99)

Why are new drugs needed?

The changed context of drug discovery and development

Drug discovery/development process

volunteer studies; patient studies lessons & development

regulatory process marketing

post registration monitoring

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

Approaches to drug discovery

Genomics; identification of receptors; gene therapy; recombinant materials;

USE iterative approach

+ transduction system (second messenger; enzyme)

functional whole or part organs

ISOLATED TISSUE EXPERIMENTS

WHOLE ANIMAL EXPERIMENTS

Animal models of efficacy

GET INTO MAN EARLY

Reducing animal usage

3Rs -- 3Rs -- 3Rs

Chemical and biological characterisation

Safety & toxicity in animals

Volunteer studies (phase I trials)

Volunteer studies (phase I trials)

Patient studies (phase 2 trials)

Patient studies (phase 3 trials)

others:-- matched pairs; combinations; ++

The Regulatory process

Classic sales curve

appreciate where best used and risks

Lessons and development

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