Drug development

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5 Δεκ 2012 (πριν από 4 χρόνια και 8 μήνες)

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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

marketing

post registration

monitoring

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 + 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

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; ++

A

B

A

A

B

B

B

A

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 effects

adverse reactions

wonder drug

no side effects

not always

effective

appreciate where best

used and risks

balanced view of

advantages &

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