L13 - Drug Discovery and Development

Question 1

4 stages of new drug development

Answer 1

Basic research and target selection (3 years)
Preclinical research (3 years)
Clinical development phase 1-3 (6-7 years)
Regulatory review (1-2 years)

Question 2

New drug development research is carried out by

Answer 2

Large pharmaceutical companies

Contract research organisations

Question 3

Drug discovery - target selection

Answer 3

Receptors
Enzymes
Transport proteins

Question 4

Drug discovery - lead finding

Answer 4

Invitro assay performed on an expressed human gene that generates the target
Amenable to high throughput screening practices - fast, reliable and reproducible

Question 5

Drug discovery - lead finding techniques

Answer 5

Read out of receptor activity using light absorption techniques
Monitor enzyme activity
Automated screens against chemical libraries
Specific interaction between drug and identified protein target

Question 6

Drug discovery - lead molecule optimisation

Answer 6

Improve target specificity
Improve potency and affinity to drug target
Pharmaceutical and pharmacokinetic properties
Reduced safety liabilities

Question 7

Toxicology and safety of the molecule - lead selection - exploratory toxicology

Answer 7

General toxicity in silico and in vitro – how drug interacts with different proteins
Preliminary genotoxicity – will drug cause mutations
Preliminary toxicity in vivo – animal experiments

Question 8

Toxicology and safety of the molecule - lead selection - exploratory safety

Answer 8

Off target binding profile – unexpected effects
Preliminary CV safety
Preliminary CNS safety

Question 9

Toxicology and safety of the molecule - preclinical development - regulatory toxicology

Answer 9

50% of drugs fail
Genotoxicity – how drug interacts within mammals
Toxico/pharmacokinetics
General toxicity

Question 10

Toxicology and safety of the molecule - preclinical development - regulatory safety

Answer 10

Respiratory
CV safety
CNS safety
Must maintain GLP – good laboratory practice

Question 11

Toxicology and safety of the molecule - clinical development - regulatory toxicology

Answer 11

Carcinogenicity
Reproductive/juvenile toxicology
Immune-phototoxicity abuse studies
Repeat dose toxicity

Question 12

Drug discovery - exploratory studies - in vitro - mutagenicity

Answer 12

Ames test
Various strains of salmonella cannot grow on a media that is missing histamine
If bacteria grow, drug may have caused mutations that reverse this effect

Question 13

Drug discovery - exploratory studies - in vitro - arrhythmia biomarker

Answer 13

Look to see if the drug can interfere with hERG potassium ion channel
Drugs that bind to this channel give rise to Long QT syndrome

Question 14

Drug discovery - exploratory studies - in vivo

Answer 14

Repeat administration for 14 days in animal model

Every tissue in animal model will be compared to an untreated animal under microscopy

Question 15

Preclinical - biomolecule vs small molecule

Answer 15

Both undergo 1-3 and 6 month studies

Range finding and developmental toxicity studies

Question 16

Small molecule – 70%

Answer 16

1 year non-rodent
Genotoxicity studies – how the host immune system reacts to the drug
Carcinogenicity and route specific studies
o

Question 17

Biomolecule – 30%

Answer 17

Immunogenicity – how the protein will be accepted by the host
Action dependent
Post translation modifications occur – cant use predication as you can with small molecules
Don’t expect toxic metabolites so safety precautions easier
Don’t enters cells so can’t cause mutations
Need to check its binding in every single tissue

Question 18

Small molecule time scale

Answer 18

Time 4.5–5 years

Question 19

Biomolecule time scale

Answer 19

Time 2-2.5 years

Question 20

Preclinical - goals of non-clinical safety evaluations

Answer 20

Toxicity
Toxicokinetics
Maximum non-toxic dose and minimum affective dose
Dose selection for first use in humans
Identification of specific monitoring requirements

Question 21

Preclinical - general toxicology - clinical pathology

Answer 21

Changes in haematology/clinical chemistry
Changes in kidney and liver function
Changes in blood coagulation

Question 22

Preclinical - general toxicology - pathology

Answer 22

Large organ toxicity

Question 23

Preclinical - animal toxicology - small molecules

Answer 23

Must adhere to the 3R’s – reduce, refine, replace
Rodent – rat
Non rodent – beagle

Question 24

Three dose groups

Answer 24

Low – no toxicology
Intermediate
High – toxicology expected in target organ

Question 25

Preclinical - animal toxicology - biopharmaceuticals

Answer 25

Off target toxicology uncommon Adverse reactions - Exaggerated pharmacology – due to high specificity of the molecules - Anti-drug antibody response - Accelerated clearance - Prolongation of exposure - Neutralise the pharmacological activity

Question 26

Preclinical - immunotoxicology - small molecule

Answer 26

``` Unexpected and due to off target effect Indicators in standard toxicology Haematological change Weight change Histophathology – spleen, lymph node, infections ```

Question 27

Preclinical - immunotoxicology - biopharmaceutical

Answer 27

Thorough understanding required to anticipate risk Infusion reaction Cytokine storm – when drug injected for the first time Immunosuppression Autoimmunity

Question 28

Immunotoxicology example

Answer 28

Monoclonal antibody developed by TeGenero Designed against receptor on T cells aim to switch the receptor on to treat Leukaemia Dose – 500 times lower than minimum dose tested in animal models Within 1 hour the patients collapsed – cytokine storm (full blood transfusions as treatment) 1 amino acid change which was not identified in the animal model caused this effect

Question 29

Preclinical - safety pharmacology

Answer 29

Any undesirable effects on physiological functions Cardiovascular system – in vitro and in vivo Central nervous system – rat Respiratory system – rat

Question 30

Preclinical – CNS pharmacology – Irwin activity screen

Answer 30

3 dose levels + control group – observe for 4-6 hours Physical factors and gross appearance Observation of behaviour o In novel environment o In response to stimuli Measures recorded during supine restraint Grip strength, motor coordination and locomotor activity Bizarre behaviour Seizures

Question 31

Preclinical - cardiovascular pharmacology

Answer 31

In vitro electrophysiology to screen for QT prolongation – hERG assay In vivo assessment of QT – non rodent CV telemetry

Question 32

Preclinical - genetic toxicology

Answer 32

In vitro and in vivo tests designed to detect compounds that induce genetic damage Damage to DNA - E.g. gene mutation, chromosomal damage, recombination - Predicts potential for malignancy or genetic effects Ames test sufficient for first administration in human (single dose)

Question 33

Preclinical - pharmacokinetics

Answer 33

AMDE – elimination studies not necessary before FIK Drug metabolism - In vitro and In vivo - Looking for species specific metabolites

Question 34

Conclusions before human trials

Answer 34

Evidence of pharmacological activity Maximum non-toxic dose Adverse effects on target organs Relationship of effects to dose and exposure Differences observed in different species Evaluation of risk in humans

Question 35

Why is regulation needed - Elixir sulfanilamide – 1937

Answer 35

Contained Diethylene Glycol, killing 107

Question 36

Why is regulation needed - Sulfathiazole tablets – 1941

Answer 36

Contained the sedative Phenobarbital, killing 300 | Control deficiencies in the plant and irregularities in the firms attempt to recall the drug

Question 37

Why is regulation needed - Thalidomide – 1962

Answer 37

Sleeping pill caused severe birth defect of arms and legs 1954 - first synthesized 1957 - launched sleeping tablet Contergan 1961 - withdrawn from markets

Question 38

Clinical trials phase 1

Answer 38

Is it safe How well is it tolerated What are the pharmacokinetic properties How well is the drug is reaching its intended target

Question 39

Clinical trials phase 2

Answer 39

Few hundred patients How much should be given to be effective How well does the treatment work in people with the condition

Question 40

Clinical trials phase 3

Answer 40

1000+ patients Definitive results Multi-centre and multi-national trials Patients continually monitored for toxic side effects – individual variability seen Patients also given placebos and other previously used drugs Application for approval and marketing

Question 41

Phase 4

Answer 41

Post marketing surveillance – helps direct the labelling of the product Detect rare or long term adverse effects

Question 42

5 withdrawn drugs

Answer 42

``` Sibutramine Propoxyphene Drotrecogin alfa Rimonabant Hydromorphone ```

Question 43

Sibutramine

Answer 43

Appetite suppressant | Heart attack and stroke

Question 44

Propoxyphene

Answer 44

Opioid painkiller | Heart attack and stroke

Question 45

Drotrecogin alfa

Answer 45

Sepsis | No benefit

Question 46

Rimonabant

Answer 46

Anti-obesity drug | Severe depression and suicide

Question 47

Hydromorphone

Answer 47

Narcotic painkiller | High risk of accidental overdose with alcohol

Question 48

% success rate of new drugs

Answer 48

11% of all drugs that go through this process succeed Cardiovascular drugs have the highest % success rate CNS drugs have a lower % success rate

Question 49

Commercial problems

Answer 49

20% of new drugs are failing on a commercial basis - not economically viable Should now be improving as companies better align functions

Question 50

Clinical efficacy problems

Answer 50

30% of new drugs do not help the problem | Target identification and validation wrong

Question 51

DMPK problems

Answer 51

10% of new drugs do not have the pharmacokinetic properties we need