Week 3 Part 2 Flashcards
For preclinical safety testing, who are the species of interest?
Humans (patients)
Who are the essential stepping stone to explore the safety of potential new medicines at dose/conc in excess of clinical efficacy ?
Animals
What are the goals of preclinical safety testing?
- Identify and eliminate compounds that carry a high safety risk to patients
- Identify key organs associated with toxicity and biomarkers to support clinical monitoring
- Define these relationships to exposure and predict the therapeutic index
- Understand the underlying mechanisms of any toxicity
What is the purpose of toxicology?
Understand safety of the drug
What are the 3 key organs in the body associated with toxicology?
- Brain
- Heart
- Lungs
Who is Philippus Aureolus?
- Swiss German - stubborn and independent
- Renaissance physician, botanist, alchemist, astrologer
- Credited for giving zinc its name - zincum
- Founder of toxicology - Dosis fact venenum
What is the importance of dose
6l of water will kill you
US women died by water intoxication
Contestants were first given 8 ounce (225 millilitre) bottles to drink every 15 minutes
She died because of hyponatremia ([Na] decrease)
What is Botulinum toxin ?
What is Botulinum toxin
- Neurotoxin protein
- Human LD50 1.2-2.1 ng/kg IV and 10-13 ng/kg
- Blocks release of ACH
- Use to treat muscle severe muscle paralysis
- Cosmetic industry - reduces wrinkles
What can molecules be?
Incredibly hazard (Botox)
What is toxicology?
Marriage between hazard and risk
Define Toxikon
The poison
Define Toxicity
The inherent adverse effects of a material
Define Toxicology
The science of understanding how substances can harm life
Define hazard
The potential of an inherently adverse material to cause damage under conditions of the proposed use
Define risk
A measure of the probability that harm will occur under defined conditions of exposure to a chemical
What is toxicology?(graph)
Very risk adverse
You do not take the middle and you do not take the far inched
You look at the other limits
What is Hill-coefficient?
The level of sigmoidicity of the curve
Steep curve of Hill-coefficient
High hill number
Shallow curve of the Hill-coefficient
Smaller hill number
What are the fatal flaw drugs you want to rule out?
Narrow Therapeutic index
Very steep dose-response
What does the acceptable (exposure) margin for each new drug depend on?
- Risk vs Benefit
2. Target clinical population and therapeutic area (e.g. oncology vs inflammation)
Define Therapeutic Index
A ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is effective
What are the 2 terms in term of dose ?
- LOAEL
2. NOAEL
LOAEL
Lowest observed adverse effect level
NOAEL
No observed adverse effect level
What happens during drug development?
Things rarely improve
They often get worse
No opportunity to re-engineer in development
Issues in development become hurdle for discovery
Thorough and complete understanding of underlying biology is paramount
What has a low TI?
Anti-cancer drugs
They are toxic molecules
What is Mabel used for?
Monoclonal antibodies and gene therapy
Can’t measure pharmacokinetic
Looking at biological effect
MABEL
Minimum anticipated biological effect level
Anticipated dose level leading to minimal biological effect in humans
Mandated approach for new drugs with pleotropic effects e.g. targeting immune system and blood coagulation system
What are the safety evaluation studies?
- General toxicology
- Safety Pharmacology
- Genotoxicity
- Reproductive toxicology
- Juvenile toxicology
- Carcinogenicity toxicology
General toxicology
Safety in the whole organism
Safety Pharmacolofy
Effect of drug on physiology
CNS, cardiovascular and respiratory assessment
Genotoxicity
Effects on genetic material
Reproductive toxicology
Effect on fertility
Embryo-foetal
Peri-postnatal development
Juvenile toxicology
To support paediatric use
carcinogenicity toxicology
Potential for induction of tumours
Why are the safety testing very much dependent on use of animals?
- Large regulatory data base and extensive knowledge
- Use rodent - typically rat
- Non rodent - dogs, primate or mini-pig
What does the choice of non-rodent species depend on?
- Relevant target pharmacology
- Similarity in metabolism and disposition
- Relative exposures
What is noise used for ?
Carcinogenic studies
What has a similar immune system to humans?
- Mini-pigs
2. Primates
Where is target not expressed in?
Neither rat or dog
Studies not done on these species
What are studies performed to?
Good Laboratory Practice (GLP)
What are GLP?
- regulatory set of principles that provided a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived
What is the main purpose of GLP?
Ability to recreate the experiment
Not scientific quality/study design
What is International Conference on Harmonisation mission?
Make recommendation towards achieving greater harmonisation in interpretation and application of technical guideline and requirement for pharmaceutical product registration
Reducing duplication of testing carried out during research and development of new human medicine
What are the non-clinical safety guidance?
- Carcinogenicity studies S1A-S1C
- Genotoxicity studies S2
- Toxicokinetics and Pharmacokinetics S3A-S3B
- Toxicity testing S4
- Reproductive toxicology S5
- Biotechnology products S6
- Safety pharmacology studies S7A and S7B
- Immunotoxicology studies S8
- Nonclinical evaluation for anti cancer pharmaceutical S9
- Photosafety evaluation S10
What are the toxicity of the whole organisms with endpoints focuses on?
- Clinical signs and physical examination
- Ophthalmology
- Electrocardiography
- Body weight/food consumption
- Clinical pathology
- Post mortrm investigations
What are examples of clinical signs and physical examination
General appearance Behaviour Posture Locomotion CNS GI Respiratory Body temperature Behavioural batteries Water consumption
Electrocardiography
Predict arrhythmia
Body weight/ food consumption
Quantitative indicators of chronic toxicity
Clinical pathology
Haematology
Clinical chemistry
Urinalysis
Post-Mortem investigation
Necropsy
Organ weights
Histopathology
Target organ toxicity
What is single dose/rising toxicity?
Relationship between dose/exposure and effect
Rodent and non-rodent
Repeat dose studies
Target organs 2 week to 12 months
Rodent and non-rodent
What does mutagenicity assays detect?
Gene level changes
Define mutagen
Heritable change in the organisms DNA sequence
What does cytogenetic assay detect?
Chromosome level changes
Wha are 2 types of cytogenetic assays ?
- Aneugen
2. Clastogen
What is aneugen?
Causes gain or loss of one or more whole chromosomes from the normal number of chromosomes
What is clastogen?
Induced chromosomal damage resulting in gain, loss or rearrangement of chromosome pieces
What is PK?
What body does to drug
What is pharmacodynamics
What the drug does to body
What are the 3 categories pharmacology studies can be divided into?
- Primary pharmacodynamic
- Secondary pharmacodynamic
- Safety pharmacology studies
What is the definition of safety pharmacology studies?
Investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above
What does the safety pharmacology focus on?
- Cardiovascular - heart
- Pulmonary - lungs
- CNS - brain
What is classic approach?
- Define and understand the drug concentration (or exposure) at which the compound is predicted to be efficacious
- Should provide best maximal clinical efficacy and a clinically differentiated profile
- improvement over sOC
How is classic approach achieved?
- Integrate data and models
- in vitro, in-vivo, systems, safety, comparator, differentiation etc
- quantitative understanding of drug class/ or mechanism
- confidence in pre-clinical to clinical translation and to clinical outcome
What is regulatory guidance ?
Guidance for industry
How you set your safe starting dose
What does adverse drug events cause?
Estimated 6.5% of unplanned hospital admissions in the UK
Account for 4% of hospital bed capacity
DDI
Altered metabolism or transport affecting drug concentration
Relatively difficult to manage - potentially fatal
What is drug-drug interaction?
A change in a drugs effect on the body when the drug is taken together with a second drug
Can delay, decrease or enhance absorption of either drug
Can cause adverse effects
Within the patients group surveyed for DDI?
- 33 DDI identified for drug recommended in type 2 diabetes guidelines
- 89 for depression
- 111 for heart failure
What are examples of red inhibitors?
- Bupropion
- Fluoxetine
- Paroxetine
- Quinidine
CYP2D6
What does a strong inhibitor cause?
> 5 fold increase in the plasma AUC values or more than 80% decrease in clearance
What does a moderate inhibitor cause?
A >2 fold increase in the plasma AUC values or 50-80% decrease in clearance
What does a weak inhibitor cause?
> 1.25 fold
But <2 fold increase in the plasma AUC values or 20-50% decrease in clearance
What is Terfenadine?
Cardiotoxic
It was metabolised to carboxyTerfenadine
Caused non-sedating anti-histamine effect
Metabolism was mediated br CYP3A4
What is ketoconazole?
Most potent 3A4 inhibitor
Used in FDA guidance
Alters the metabolism of terfenadine and results in accumulation of unmetaboljsed parent drug which is associated with induction of potentially lethal ventricular arrhythmia
What did Seldane reach?
Peak sales of $540 million by 1992
Effectively a pro-drug
For paracetamol overdose what are patients given?
Methionine or vitamin C
It is a scavenger for free radicals to mop up that free metabolite
What are opioid active?
Morphine
Morphine-6-glucoronide
Rule of Thumb
The loser the dose the better
Low interaction with P450
Want a high IC50
