Week 3 Part 2 Flashcards
(83 cards)
1
Q
For preclinical safety testing, who are the species of interest?
A
Humans (patients)
2
Q
Who are the essential stepping stone to explore the safety of potential new medicines at dose/conc in excess of clinical efficacy ?
A
Animals
3
Q
What are the goals of preclinical safety testing?
A
- 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
4
Q
What is the purpose of toxicology?
A
Understand safety of the drug
5
Q
What are the 3 key organs in the body associated with toxicology?
A
- Brain
- Heart
- Lungs
6
Q
Who is Philippus Aureolus?
A
- Swiss German - stubborn and independent
- Renaissance physician, botanist, alchemist, astrologer
- Credited for giving zinc its name - zincum
- Founder of toxicology - Dosis fact venenum
7
Q
What is the importance of dose
A
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)
8
Q
What is Botulinum toxin ?
A
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
9
Q
What can molecules be?
A
Incredibly hazard (Botox)
10
Q
What is toxicology?
A
Marriage between hazard and risk
11
Q
Define Toxikon
A
The poison
12
Q
Define Toxicity
A
The inherent adverse effects of a material
13
Q
Define Toxicology
A
The science of understanding how substances can harm life
14
Q
Define hazard
A
The potential of an inherently adverse material to cause damage under conditions of the proposed use
15
Q
Define risk
A
A measure of the probability that harm will occur under defined conditions of exposure to a chemical
16
Q
What is toxicology?(graph)
A
Very risk adverse
You do not take the middle and you do not take the far inched
You look at the other limits
17
Q
What is Hill-coefficient?
A
The level of sigmoidicity of the curve
18
Q
Steep curve of Hill-coefficient
A
High hill number
19
Q
Shallow curve of the Hill-coefficient
A
Smaller hill number
20
Q
What are the fatal flaw drugs you want to rule out?
A
Narrow Therapeutic index
Very steep dose-response
21
Q
What does the acceptable (exposure) margin for each new drug depend on?
A
- Risk vs Benefit
2. Target clinical population and therapeutic area (e.g. oncology vs inflammation)
22
Q
Define Therapeutic Index
A
A ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is effective
23
Q
What are the 2 terms in term of dose ?
A
- LOAEL
2. NOAEL
24
Q
LOAEL
A
Lowest observed adverse effect level
25
NOAEL
No observed adverse effect level
26
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
27
What has a low TI?
Anti-cancer drugs
| They are toxic molecules
28
What is Mabel used for?
Monoclonal antibodies and gene therapy
Can’t measure pharmacokinetic
Looking at biological effect
29
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
30
What are the safety evaluation studies?
1. General toxicology
2. Safety Pharmacology
3. Genotoxicity
4. Reproductive toxicology
5. Juvenile toxicology
6. Carcinogenicity toxicology
31
General toxicology
Safety in the whole organism
32
Safety Pharmacolofy
Effect of drug on physiology
| CNS, cardiovascular and respiratory assessment
33
Genotoxicity
Effects on genetic material
34
Reproductive toxicology
Effect on fertility
Embryo-foetal
Peri-postnatal development
35
Juvenile toxicology
To support paediatric use
36
carcinogenicity toxicology
Potential for induction of tumours
37
Why are the safety testing very much dependent on use of animals?
1. Large regulatory data base and extensive knowledge
2. Use rodent - typically rat
3. Non rodent - dogs, primate or mini-pig
38
What does the choice of non-rodent species depend on?
1. Relevant target pharmacology
2. Similarity in metabolism and disposition
3. Relative exposures
39
What is noise used for ?
Carcinogenic studies
40
What has a similar immune system to humans?
1. Mini-pigs
| 2. Primates
41
Where is target not expressed in?
Neither rat or dog
| Studies not done on these species
42
What are studies performed to?
Good Laboratory Practice (GLP)
43
What are GLP?
1. regulatory set of principles that provided a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived
44
What is the main purpose of GLP?
Ability to recreate the experiment
| Not scientific quality/study design
45
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
46
What are the non-clinical safety guidance?
1. Carcinogenicity studies S1A-S1C
2. Genotoxicity studies S2
3. Toxicokinetics and Pharmacokinetics S3A-S3B
4. Toxicity testing S4
5. Reproductive toxicology S5
6. Biotechnology products S6
7. Safety pharmacology studies S7A and S7B
8. Immunotoxicology studies S8
9. Nonclinical evaluation for anti cancer pharmaceutical S9
10. Photosafety evaluation S10
47
What are the toxicity of the whole organisms with endpoints focuses on?
1. Clinical signs and physical examination
2. Ophthalmology
3. Electrocardiography
4. Body weight/food consumption
5. Clinical pathology
6. Post mortrm investigations
48
What are examples of clinical signs and physical examination
```
General appearance
Behaviour
Posture
Locomotion
CNS
GI
Respiratory
Body temperature
Behavioural batteries
Water consumption
```
49
Electrocardiography
Predict arrhythmia
50
Body weight/ food consumption
Quantitative indicators of chronic toxicity
51
Clinical pathology
Haematology
Clinical chemistry
Urinalysis
52
Post-Mortem investigation
Necropsy
Organ weights
Histopathology
Target organ toxicity
53
What is single dose/rising toxicity?
Relationship between dose/exposure and effect
Rodent and non-rodent
54
Repeat dose studies
Target organs 2 week to 12 months
| Rodent and non-rodent
55
What does mutagenicity assays detect?
Gene level changes
56
Define mutagen
Heritable change in the organisms DNA sequence
57
What does cytogenetic assay detect?
Chromosome level changes
58
Wha are 2 types of cytogenetic assays ?
1. Aneugen
| 2. Clastogen
59
What is aneugen?
Causes gain or loss of one or more whole chromosomes from the normal number of chromosomes
60
What is clastogen?
Induced chromosomal damage resulting in gain, loss or rearrangement of chromosome pieces
61
What is PK?
What body does to drug
62
What is pharmacodynamics
What the drug does to body
63
What are the 3 categories pharmacology studies can be divided into?
1. Primary pharmacodynamic
2. Secondary pharmacodynamic
3. Safety pharmacology studies
64
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
65
What does the safety pharmacology focus on?
1. Cardiovascular - heart
2. Pulmonary - lungs
3. CNS - brain
66
What is classic approach?
1. Define and understand the drug concentration (or exposure) at which the compound is predicted to be efficacious
2. Should provide best maximal clinical efficacy and a clinically differentiated profile
- improvement over sOC
67
How is classic approach achieved?
1. 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
68
What is regulatory guidance ?
Guidance for industry
| How you set your safe starting dose
69
What does adverse drug events cause?
Estimated 6.5% of unplanned hospital admissions in the UK
| Account for 4% of hospital bed capacity
70
DDI
Altered metabolism or transport affecting drug concentration
Relatively difficult to manage - potentially fatal
71
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
72
Within the patients group surveyed for DDI?
1. 33 DDI identified for drug recommended in type 2 diabetes guidelines
2. 89 for depression
3. 111 for heart failure
73
What are examples of red inhibitors?
1. Bupropion
2. Fluoxetine
3. Paroxetine
4. Quinidine
CYP2D6
74
What does a strong inhibitor cause?
> 5 fold increase in the plasma AUC values or more than 80% decrease in clearance
75
What does a moderate inhibitor cause?
A >2 fold increase in the plasma AUC values or 50-80% decrease in clearance
76
What does a weak inhibitor cause?
> 1.25 fold
| But <2 fold increase in the plasma AUC values or 20-50% decrease in clearance
77
What is Terfenadine?
Cardiotoxic
It was metabolised to carboxyTerfenadine
Caused non-sedating anti-histamine effect
Metabolism was mediated br CYP3A4
78
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
79
What did Seldane reach?
Peak sales of $540 million by 1992
Effectively a pro-drug
80
For paracetamol overdose what are patients given?
Methionine or vitamin C
| It is a scavenger for free radicals to mop up that free metabolite
81
What are opioid active?
Morphine
| Morphine-6-glucoronide
82
Rule of Thumb
The loser the dose the better
83
Low interaction with P450
Want a high IC50
