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Physiology And Pharmacology Of Systems > Toxicology and the role of safety evaluation in drug discovery and development > Flashcards

Toxicology and the role of safety evaluation in drug discovery and development Flashcards

1
Q

Definition of efficacy

A

Max response achievable from an applied or dosed agent

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2
Q

Definition of toxicity

A

Refers to how poisonous/harmful a substance can be
Drug toxicity occurs when a person has accumulated too much drug in the bloodstream leading to adverse effects on the body

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3
Q

Definition of adverse drug event (ADE)

A

Injury resulting from medical intervention related to a drug

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4
Q

Definition of Food and Drug Administration (FDA)

A

US government agency that protects public health by ensuring the safety, efficacy and security of drugs and medical devices

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5
Q

Definition of the Ministry of Health, Labour and Welfare (MHLW)

A

Japanese group that protects public health by ensuring safety, efficacy and security of drugs and medical devices

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6
Q

Definition of ICH S7A safety pharmacology studies

A

Document providing definitions, general principles and recommendations for safety pharmacology studies

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7
Q

Definition of max tolerated dose (MTD)

A

Highest dose that will produce the desired effect without unacceptable toxicity

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8
Q

Definition of no observed adverse effect level (NOAEL)

A

Level of exposure of an organism where there is no biological/statistically significant increase in frequency/severity of adverse effects

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9
Q

What is safe

What is the probability of an adverse event

A

There is no such thing as safe
All drugs have benefits and risks

Probability of an adverse event = total exposure x likelihood

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10
Q

What does the benefit:risk ratio depend on

A
  • Efficacy
  • Toxicity
  • Disease
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11
Q

How is drug safety achieved

A

Hazard identification (what needs to be controlled)

Risk assessment (why is it a risk, who will this affect)

Risk management (how to reduce the risk)

Hazard monitoring (has the hazard happened again even when managed, are there any new hazards)

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12
Q

Who is involved in drug safety management

A 
Researchers
Clinicians
Patients
Regulators (watch process carefully)
Experts (help with process)
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13
Q

How can you manage risks

A

Identify the risk
Find ways of reducing the risk, doesnt have to be a hug change
If benefit:risk ratio is too low, drug can be removed from the market

Patient groups can get drugs back on the market if the benefits still outweigh the risks but are monitored more closely to reduce ADE

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14
Q

How are drugs regulated

A

Legal contract based on benefit:risk ratio

Between Health Authorities and the pharmaceutical company

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15
Q

Who are the Health Authorities and what do they do

A

FA, EMFA, MHLW

  • Represent society
  • Protects public health, safety from the investigation of a new drug (IND) => new drug application (NDA) and marketing authorization application (MAA)
  • Monitors non compliance
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16
Q

How are the pharmaceutical companies involved in drug regulation

A
  • Applies for permission to market drugs in a specific indication
  • Owns documentation used in assessment
  • Collects, compiles and evaluates safety and quality data
17
Q

How and where does safety evaluation occur in drug discovery and development

A

All stages

Design, select, develop best compounds as new drugs
Understand exposure, response relationships for effects that may be predictive of adverse events in humans
Protect clinical trial population and patients from potential AE
Understand AE mechanisms in trials and throughout the lifecycle of the drug

18
Q

How is safety designed into the drug in early stage safety evaluations

A

Target info from knock out, mutational and SNP studies
Chemotype info: structure, activity relationship, toxicity flags and selectivity
Test compounds: selectivity and specificity
Rational design of selective, specific molecules
Knowledge of likely liabilities but limited exposure in vivo

19
Q

What happens in late discovery stage safety evaluations in clinical trials

A

Assessment of

  • Tolerability: wide range doses, chronic dosing, disease models
  • Cardiac Integrated Risk Assessment (hERG, Purkinje, Lagendorff)
  • Genotoxicity risk in vitro

Tests and uses

  • Broader, more speculative selectivity in vitro
  • ICH S7A safety pharmacology studies
  • 7-28 day toxicity in 2 species to define MTD and NOAEL
20
Q

What is needed before Phase I can start

A

Clinical trial application (CTA), Investigative Brochure (IB)
Approval from ethics committee
-NOAEL, MABEL calculations: first dose based on safety window

21
Q

What is the purpose of Phase I regarding safety

A

Find out

  • Frequency and severity of treatment, AEs
  • Work out dose range in normal subjects
  • Human drug metabolism pharmacokinetic (DMPK) and proof of mechanism (POM)
22
Q

What is the purpose of Phase II regarding safety

A

Longer duration, larger groups for efficacy determination
Supported by longer term detailed toxicity studies
Potential to identify biomarkers of efficacy, toxicity
Determine commercial profile for further investment
ADR monitoring starts
Pharmacovigilance starts here

23
Q

How do you calculate the probability of detecting an ADE

A

Probability of detecting event = total exposure x likelihood

24
Q

Describe the probability of a drug having efficacy

A

On target pharmacology generally has high likelihood on effect

25
Q

Describe the probability of safety pharamcology

A

On target and off target pharmacology have high likelihoods of effect
However, this may need greater exposure

26
Q

Describe the probability of a drugs toxicology

A

Idiosyncratic, lower likelihood events need high exposure and larger group sizes

27
Q

Describe the probabilities related to pharmacovigilance

A

Some ADR may only be detectable by the post marketing surveillance
The longer a drug is around, more likely to detect ADR

28
Q

What happens if an ADR does happen

A

Report them via Yellow Card Scheme

29
Q

What is always found in the package insert leaflet

A

1 side effect is always about allergies

Physiology And Pharmacology Of Systems (22 decks)

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