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DDD x > Week 3 Part 2 > Flashcards

Week 3 Part 2 Flashcards

1
Q

For preclinical safety testing, who are the species of interest?

A

Humans (patients)

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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

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3
Q

What are the goals of preclinical safety testing?

A
  1. Identify and eliminate compounds that carry a high safety risk to patients
  2. Identify key organs associated with toxicity and biomarkers to support clinical monitoring
  3. Define these relationships to exposure and predict the therapeutic index
  4. Understand the underlying mechanisms of any toxicity
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4
Q

What is the purpose of toxicology?

A

Understand safety of the drug

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5
Q

What are the 3 key organs in the body associated with toxicology?

A
  1. Brain
  2. Heart
  3. Lungs
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6
Q

Who is Philippus Aureolus?

A
  1. Swiss German - stubborn and independent
  2. Renaissance physician, botanist, alchemist, astrologer
  3. Credited for giving zinc its name - zincum
  4. Founder of toxicology - Dosis fact venenum
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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)

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8
Q

What is Botulinum toxin ?

A

What is Botulinum toxin

  1. Neurotoxin protein
  2. Human LD50 1.2-2.1 ng/kg IV and 10-13 ng/kg
  3. Blocks release of ACH
  4. Use to treat muscle severe muscle paralysis
  5. Cosmetic industry - reduces wrinkles
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9
Q

What can molecules be?

A

Incredibly hazard (Botox)

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10
Q

What is toxicology?

A

Marriage between hazard and risk

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11
Q

Define Toxikon

A

The poison

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12
Q

Define Toxicity

A

The inherent adverse effects of a material

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13
Q

Define Toxicology

A

The science of understanding how substances can harm life

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14
Q

Define hazard

A

The potential of an inherently adverse material to cause damage under conditions of the proposed use

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15
Q

Define risk

A

A measure of the probability that harm will occur under defined conditions of exposure to a chemical

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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

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17
Q

What is Hill-coefficient?

A

The level of sigmoidicity of the curve

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18
Q

Steep curve of Hill-coefficient

A

High hill number

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19
Q

Shallow curve of the Hill-coefficient

A

Smaller hill number

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20
Q

What are the fatal flaw drugs you want to rule out?

A

Narrow Therapeutic index

Very steep dose-response

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21
Q

What does the acceptable (exposure) margin for each new drug depend on?

A
  1. Risk vs Benefit

2. Target clinical population and therapeutic area (e.g. oncology vs inflammation)

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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

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23
Q

What are the 2 terms in term of dose ?

A
  1. LOAEL

2. NOAEL

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24
Q

LOAEL

A

Lowest observed adverse effect level

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25
Q

NOAEL

A

No observed adverse effect level

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26
Q

What happens during drug development?

A

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

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27
Q

What has a low TI?

A

Anti-cancer drugs

They are toxic molecules

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28
Q

What is Mabel used for?

A

Monoclonal antibodies and gene therapy

Can’t measure pharmacokinetic

Looking at biological effect

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29
Q

MABEL

A

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

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30
Q

What are the safety evaluation studies?

A
  1. General toxicology
  2. Safety Pharmacology
  3. Genotoxicity
  4. Reproductive toxicology
  5. Juvenile toxicology
  6. Carcinogenicity toxicology
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31
Q

General toxicology

A

Safety in the whole organism

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32
Q

Safety Pharmacolofy

A

Effect of drug on physiology

CNS, cardiovascular and respiratory assessment

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33
Q

Genotoxicity

A

Effects on genetic material

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34
Q

Reproductive toxicology

A

Effect on fertility
Embryo-foetal
Peri-postnatal development

35
Q

Juvenile toxicology

A

To support paediatric use

36
Q

carcinogenicity toxicology

A

Potential for induction of tumours

37
Q

Why are the safety testing very much dependent on use of animals?

A
  1. Large regulatory data base and extensive knowledge
  2. Use rodent - typically rat
  3. Non rodent - dogs, primate or mini-pig
38
Q

What does the choice of non-rodent species depend on?

A
  1. Relevant target pharmacology
  2. Similarity in metabolism and disposition
  3. Relative exposures
39
Q

What is noise used for ?

A

Carcinogenic studies

40
Q

What has a similar immune system to humans?

A
  1. Mini-pigs

2. Primates

41
Q

Where is target not expressed in?

A

Neither rat or dog

Studies not done on these species

42
Q

What are studies performed to?

A

Good Laboratory Practice (GLP)

43
Q

What are GLP?

A
  1. regulatory set of principles that provided a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived
44
Q

What is the main purpose of GLP?

A

Ability to recreate the experiment

Not scientific quality/study design

45
Q

What is International Conference on Harmonisation mission?

A

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
Q

What are the non-clinical safety guidance?

A
  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
Q

What are the toxicity of the whole organisms with endpoints focuses on?

A
  1. Clinical signs and physical examination
  2. Ophthalmology
  3. Electrocardiography
  4. Body weight/food consumption
  5. Clinical pathology
  6. Post mortrm investigations
48
Q

What are examples of clinical signs and physical examination

A 
General appearance 
Behaviour 
Posture 
Locomotion 
CNS
GI
Respiratory 
Body temperature 
Behavioural batteries 
Water consumption
49
Q

Electrocardiography

A

Predict arrhythmia

50
Q

Body weight/ food consumption

A

Quantitative indicators of chronic toxicity

51
Q

Clinical pathology

A

Haematology
Clinical chemistry
Urinalysis

52
Q

Post-Mortem investigation

A

Necropsy
Organ weights
Histopathology
Target organ toxicity

53
Q

What is single dose/rising toxicity?

A

Relationship between dose/exposure and effect

Rodent and non-rodent

54
Q

Repeat dose studies

A

Target organs 2 week to 12 months

Rodent and non-rodent

55
Q

What does mutagenicity assays detect?

A

Gene level changes

56
Q

Define mutagen

A

Heritable change in the organisms DNA sequence

57
Q

What does cytogenetic assay detect?

A

Chromosome level changes

58
Q

Wha are 2 types of cytogenetic assays ?

A
  1. Aneugen

2. Clastogen

59
Q

What is aneugen?

A

Causes gain or loss of one or more whole chromosomes from the normal number of chromosomes

60
Q

What is clastogen?

A

Induced chromosomal damage resulting in gain, loss or rearrangement of chromosome pieces

61
Q

What is PK?

A

What body does to drug

62
Q

What is pharmacodynamics

A

What the drug does to body

63
Q

What are the 3 categories pharmacology studies can be divided into?

A
  1. Primary pharmacodynamic
  2. Secondary pharmacodynamic
  3. Safety pharmacology studies
64
Q

What is the definition of safety pharmacology studies?

A

Investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above

65
Q

What does the safety pharmacology focus on?

A
  1. Cardiovascular - heart
  2. Pulmonary - lungs
  3. CNS - brain
66
Q

What is classic approach?

A
  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
Q

How is classic approach achieved?

A
  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
Q

What is regulatory guidance ?

A

Guidance for industry

How you set your safe starting dose

69
Q

What does adverse drug events cause?

A

Estimated 6.5% of unplanned hospital admissions in the UK

Account for 4% of hospital bed capacity

70
Q

DDI

A

Altered metabolism or transport affecting drug concentration

Relatively difficult to manage - potentially fatal

71
Q

What is drug-drug interaction?

A

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
Q

Within the patients group surveyed for DDI?

A
  1. 33 DDI identified for drug recommended in type 2 diabetes guidelines
  2. 89 for depression
  3. 111 for heart failure
73
Q

What are examples of red inhibitors?

A
  1. Bupropion
  2. Fluoxetine
  3. Paroxetine
  4. Quinidine

CYP2D6

74
Q

What does a strong inhibitor cause?

A

> 5 fold increase in the plasma AUC values or more than 80% decrease in clearance

75
Q

What does a moderate inhibitor cause?

A

A >2 fold increase in the plasma AUC values or 50-80% decrease in clearance

76
Q

What does a weak inhibitor cause?

A

> 1.25 fold

But <2 fold increase in the plasma AUC values or 20-50% decrease in clearance

77
Q

What is Terfenadine?

A

Cardiotoxic
It was metabolised to carboxyTerfenadine
Caused non-sedating anti-histamine effect

Metabolism was mediated br CYP3A4

78
Q

What is ketoconazole?

A

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
Q

What did Seldane reach?

A

Peak sales of $540 million by 1992

Effectively a pro-drug

80
Q

For paracetamol overdose what are patients given?

A

Methionine or vitamin C

It is a scavenger for free radicals to mop up that free metabolite

81
Q

What are opioid active?

A

Morphine

Morphine-6-glucoronide

82
Q

Rule of Thumb

A

The loser the dose the better

83
Q

Low interaction with P450

A

Want a high IC50

DDD x (17 decks)

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