L13 - Drug Discovery and Development Flashcards
4 stages of new drug development
Basic research and target selection (3 years) Preclinical research (3 years) Clinical development phase 1-3 (6-7 years) Regulatory review (1-2 years)
New drug development research is carried out by
Large pharmaceutical companies
Contract research organisations
Drug discovery - target selection
Receptors
Enzymes
Transport proteins
Drug discovery - lead finding
Invitro assay performed on an expressed human gene that generates the target
Amenable to high throughput screening practices - fast, reliable and reproducible
Drug discovery - lead finding techniques
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
Drug discovery - lead molecule optimisation
Improve target specificity
Improve potency and affinity to drug target
Pharmaceutical and pharmacokinetic properties
Reduced safety liabilities
Toxicology and safety of the molecule - lead selection - exploratory toxicology
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
Toxicology and safety of the molecule - lead selection - exploratory safety
Off target binding profile – unexpected effects
Preliminary CV safety
Preliminary CNS safety
Toxicology and safety of the molecule - preclinical development - regulatory toxicology
50% of drugs fail
Genotoxicity – how drug interacts within mammals
Toxico/pharmacokinetics
General toxicity
Toxicology and safety of the molecule - preclinical development - regulatory safety
Respiratory
CV safety
CNS safety
Must maintain GLP – good laboratory practice
Toxicology and safety of the molecule - clinical development - regulatory toxicology
Carcinogenicity
Reproductive/juvenile toxicology
Immune-phototoxicity abuse studies
Repeat dose toxicity
Drug discovery - exploratory studies - in vitro - mutagenicity
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
Drug discovery - exploratory studies - in vitro - arrhythmia biomarker
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
Drug discovery - exploratory studies - in vivo
Repeat administration for 14 days in animal model
Every tissue in animal model will be compared to an untreated animal under microscopy
Preclinical - biomolecule vs small molecule
Both undergo 1-3 and 6 month studies
Range finding and developmental toxicity studies
Small molecule – 70%
1 year non-rodent
Genotoxicity studies – how the host immune system reacts to the drug
Carcinogenicity and route specific studies
o
Biomolecule – 30%
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
Small molecule time scale
Time 4.5–5 years
Biomolecule time scale
Time 2-2.5 years
Preclinical - goals of non-clinical safety evaluations
Toxicity
Toxicokinetics
Maximum non-toxic dose and minimum affective dose
Dose selection for first use in humans
Identification of specific monitoring requirements
Preclinical - general toxicology - clinical pathology
Changes in haematology/clinical chemistry
Changes in kidney and liver function
Changes in blood coagulation
Preclinical - general toxicology - pathology
Large organ toxicity
Preclinical - animal toxicology - small molecules
Must adhere to the 3R’s – reduce, refine, replace
Rodent – rat
Non rodent – beagle
Three dose groups
Low – no toxicology
Intermediate
High – toxicology expected in target organ
Preclinical - animal toxicology - biopharmaceuticals
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
Preclinical - immunotoxicology - small molecule
Unexpected and due to off target effect Indicators in standard toxicology Haematological change Weight change Histophathology – spleen, lymph node, infections
Preclinical - immunotoxicology - biopharmaceutical
Thorough understanding required to anticipate risk
Infusion reaction
Cytokine storm – when drug injected for the first time
Immunosuppression
Autoimmunity
Immunotoxicology example
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
Preclinical - safety pharmacology
Any undesirable effects on physiological functions
Cardiovascular system – in vitro and in vivo
Central nervous system – rat
Respiratory system – rat
Preclinical – CNS pharmacology – Irwin activity screen
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
Preclinical - cardiovascular pharmacology
In vitro electrophysiology to screen for QT prolongation – hERG assay
In vivo assessment of QT – non rodent CV telemetry
Preclinical - genetic toxicology
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)
Preclinical - pharmacokinetics
AMDE – elimination studies not necessary before FIK
Drug metabolism
- In vitro and In vivo
- Looking for species specific metabolites
Conclusions before human trials
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
Why is regulation needed - Elixir sulfanilamide – 1937
Contained Diethylene Glycol, killing 107
Why is regulation needed - Sulfathiazole tablets – 1941
Contained the sedative Phenobarbital, killing 300
Control deficiencies in the plant and irregularities in the firms attempt to recall the drug
Why is regulation needed - Thalidomide – 1962
Sleeping pill caused severe birth defect of arms and legs
1954 - first synthesized
1957 - launched sleeping tablet Contergan
1961 - withdrawn from markets
Clinical trials phase 1
Is it safe
How well is it tolerated
What are the pharmacokinetic properties
How well is the drug is reaching its intended target
Clinical trials phase 2
Few hundred patients
How much should be given to be effective
How well does the treatment work in people with the condition
Clinical trials phase 3
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
Phase 4
Post marketing surveillance – helps direct the labelling of the product
Detect rare or long term adverse effects
5 withdrawn drugs
Sibutramine Propoxyphene Drotrecogin alfa Rimonabant Hydromorphone
Sibutramine
Appetite suppressant
Heart attack and stroke
Propoxyphene
Opioid painkiller
Heart attack and stroke
Drotrecogin alfa
Sepsis
No benefit
Rimonabant
Anti-obesity drug
Severe depression and suicide
Hydromorphone
Narcotic painkiller
High risk of accidental overdose with alcohol
% success rate of new drugs
11% of all drugs that go through this process succeed
Cardiovascular drugs have the highest % success rate
CNS drugs have a lower % success rate
Commercial problems
20% of new drugs are failing on a commercial basis - not economically viable
Should now be improving as companies better align functions
Clinical efficacy problems
30% of new drugs do not help the problem
Target identification and validation wrong
DMPK problems
10% of new drugs do not have the pharmacokinetic properties we need
