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Physiology and Pharmacology > L13 - Drug Discovery and Development > Flashcards

L13 - Drug Discovery and Development Flashcards

1
Q

4 stages of new drug development

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

New drug development research is carried out by

A

Large pharmaceutical companies

Contract research organisations

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3
Q

Drug discovery - target selection

A

Receptors
Enzymes
Transport proteins

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4
Q

Drug discovery - lead finding

A

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

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5
Q

Drug discovery - lead finding techniques

A

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

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6
Q

Drug discovery - lead molecule optimisation

A

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

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7
Q

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

A

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

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8
Q

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

A

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

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9
Q

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

A

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

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10
Q

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

A

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

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11
Q

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

A

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

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12
Q

Drug discovery - exploratory studies - in vitro - mutagenicity

A

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

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13
Q

Drug discovery - exploratory studies - in vitro - arrhythmia biomarker

A

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

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14
Q

Drug discovery - exploratory studies - in vivo

A

Repeat administration for 14 days in animal model

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

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15
Q

Preclinical - biomolecule vs small molecule

A

Both undergo 1-3 and 6 month studies

Range finding and developmental toxicity studies

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16
Q

Small molecule – 70%

A

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

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17
Q

Biomolecule – 30%

A

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

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18
Q

Small molecule time scale

A

Time 4.5–5 years

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19
Q

Biomolecule time scale

A

Time 2-2.5 years

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20
Q

Preclinical - goals of non-clinical safety evaluations

A

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

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21
Q

Preclinical - general toxicology - clinical pathology

A

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

22
Q

Preclinical - general toxicology - pathology

A

Large organ toxicity

23
Q

Preclinical - animal toxicology - small molecules

A

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

24
Q

Three dose groups

A

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

25
Q

Preclinical - animal toxicology - biopharmaceuticals

A

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

26
Q

Preclinical - immunotoxicology - small molecule

A 
Unexpected and due to off target effect 
Indicators in standard toxicology 
Haematological change 
Weight change  
Histophathology – spleen, lymph node, infections
27
Q

Preclinical - immunotoxicology - biopharmaceutical

A

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

28
Q

Immunotoxicology example

A

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

29
Q

Preclinical - safety pharmacology

A

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

30
Q

Preclinical – CNS pharmacology – Irwin activity screen

A

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

31
Q

Preclinical - cardiovascular pharmacology

A

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

32
Q

Preclinical - genetic toxicology

A

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)

33
Q

Preclinical - pharmacokinetics

A

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

34
Q

Conclusions before human trials

A

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

35
Q

Why is regulation needed - Elixir sulfanilamide – 1937

A

Contained Diethylene Glycol, killing 107

36
Q

Why is regulation needed - Sulfathiazole tablets – 1941

A

Contained the sedative Phenobarbital, killing 300

Control deficiencies in the plant and irregularities in the firms attempt to recall the drug

37
Q

Why is regulation needed - Thalidomide – 1962

A

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

38
Q

Clinical trials phase 1

A

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

39
Q

Clinical trials phase 2

A

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

40
Q

Clinical trials phase 3

A

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

41
Q

Phase 4

A

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

42
Q

5 withdrawn drugs

A 
Sibutramine
Propoxyphene
Drotrecogin alfa 
Rimonabant
Hydromorphone
43
Q

Sibutramine

A

Appetite suppressant

Heart attack and stroke

44
Q

Propoxyphene

A

Opioid painkiller

Heart attack and stroke

45
Q

Drotrecogin alfa

A

Sepsis

No benefit

46
Q

Rimonabant

A

Anti-obesity drug

Severe depression and suicide

47
Q

Hydromorphone

A

Narcotic painkiller

High risk of accidental overdose with alcohol

48
Q

% success rate of new drugs

A

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

49
Q

Commercial problems

A

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

50
Q

Clinical efficacy problems

A

30% of new drugs do not help the problem

Target identification and validation wrong

51
Q

DMPK problems

A

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

Physiology and Pharmacology (13 decks)

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