Lecture 15

Question 1

what are the two phases of drug development

Answer 1

1- discovery phase (preclinical)

2- developmental phase (cinical)

Question 2

define toxicology

Answer 2

is the study of the adverse effects of chemical, physical

or biological agents on people, animals, and the environment.”

Question 3

Discovery Phase - Preclinical Testing

Answer 3

• Metabolic studies
• Many “in vitro” cellbased bioassays
• Animal-based safety
and toxicity testing

Question 4

Development Phase - Clinical Testing

Answer 4

• Conducted in human volunteers
• Small scale pilots
and large scale trials

Question 5

what are key questions in early pre clinical toxicity testing?

Answer 5

1- Is the Molecule Metabolised in Harmful Ways in the Body?

2- Is the Molecule Toxic During Short-or Long-term Treatment?

Question 6

Toxicological bioactivation

Answer 6

formation of toxic metabolites during the metabolism of drugs within the liver

Question 7

ethical factors in animal based drug testing

Answer 7

• Animal suffering kept to a
  minimum
  3R’s of animal use:
  Reduce, Refine, Replace

Question 8

what are the toxicological Issues that are Assessed in Animals

Answer 8

• Short-term toxicity (e.g. limited doses)
• Accumulation in body tissues
• Ability to cause allergies (sensitisation)
• Long-term toxicity (repeated dosing)
• Toxicity to unborn animals
• Cancer-causing ability (“carcinogenicity”)

Question 9

what animals are usually tested on and why

Answer 9

• rats and mice
• Affordable to maintain
• Convenient lifespan
• Genetically defined
• Large database of drug effects
• Similar to humans in drug
  handling – i.e. ADME
  (pharmacokinetic properties)

Question 10

how long for treatment on animals to predict human toxicities

Answer 10

• 1 month

Question 11

what is an alternative method of testing thats not through animals

Answer 11

• in vitro methods involving 2D cultured cells long been used in drug testing
• studying microfluidic models as alternatives to animals

Question 12

what are the key questions in clinical drug testing

Answer 12

1- Is the Molecule Safe in Healthy Human Subjects?

Question 13

what is phase 1 of clinical testing

Answer 13

• Main purpose is to assess human safety of drug
• Normally conducted in 10 to
  100 healthy volunteers
• Dose starts low, may increase
  with study progression
• Measure drug concentrations
  in blood, urine, etc

Question 14

What is phase 2 of clinical testing

Answer 14

- Main purpose is to assess
effectiveness of drug
- Normally conducted in 50-
500 disease-affected
patients
- Controls may received
existing drug in current use
- Success rate ~30%

Question 15

What is phase 3 of clinical testing

Answer 15

- Main purpose is large-scale
testing of drugs (1 - safety & 2-
effectiveness)
- Normally conducted in
>2000 disease-affected
patients
- Recruited in different cities,
countries (“multisite trial”)
- Takes 3-5 years, complex
organisation

Question 16

What is phase 4 of clinical testing

Answer 16

• Purpose is to monitor drug safety under “real-world” use patterns
• AKA “post-marketing surveillance”
• Can involve 50,000+ subjects
  (sometimes 1 million+)
• Reporting system uses doctors, pharmacists, patients to report side-effects
• Also assesses quality of life measures & economic considerations