drug discovery and development n.
Skip this Video
Loading SlideShow in 5 Seconds..
Drug discovery and development PowerPoint Presentation
Download Presentation
Drug discovery and development

Loading in 2 Seconds...

play fullscreen
1 / 31

Drug discovery and development - PowerPoint PPT Presentation

  • Uploaded on

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

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
Download Presentation

PowerPoint Slideshow about 'Drug discovery and development' - betty_james

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.

- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
drug discovery and development
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
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
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
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 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
Sources of drugs

Animal insulin (pig, cow)

growth hormone (man) (Creutzfeldt-Jakob)

Plant digitalis (digitalis purpurea - foxglove)

morphine (papaver somniferum)

Inorganic arsenic mercury


Synthetic chemical (propranolol)

biological (penicillin)

biotechnology (human insulin)

drug discovery development process
Drug discovery/development process

discovery; refinement; chemical & biological characterisation

safety & toxicity in animals; formulation development

volunteer studies; patient studies

regulatory process





post registration


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

approaches to drug discovery
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;


refinement of compounds
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
Levels of testing

DRUG + receptor

+ transduction

system (second

messenger; enzyme)



whole or

part organs



Anaesthetised or

conscious animals


animal models of efficacy
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
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.
reducing animal usage
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 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
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
Formulation studies
  • DRUG +

Additive:filler, lubricant, coating, stabiliser, colour, binder, disintegrator

Dosage form:capsule, tablet, injection, other?

Manipulate duration/profile: e.g. sustained release



Ease of use

clinical testing
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
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 trials1
Volunteer studies (phase I trials)


  • 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
Patient studies (phase 2 trials)
  • 150-350 ill people; informed consent
  • needs licence
  • maximum monitoring; full rescussitation
  • often patients where other treatment failed

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
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
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 trials1
Clinical trials

controlled or uncontrolled

open or blind













others:-- matched pairs; combinations; ++

the regulatory process
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
  • 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
Classic sales curve

Unit sales

serious side effects

adverse reactions

balanced view of

advantages &


wonder drug

no side effects

not always


appreciate where best

used and risks


post registration monitoring
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
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
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
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