Drug development

Question 1

Drug toxicity types

Answer 1

• Systemic toxicity (acute/ chronic)
• Carcinogenic effects
• Teratogenic effects/ reproductive toxicity

Question 2

Acute systemic toxicity

Answer 2

Single dose, 14 day period, 3 dose levels
2 mammalian species
Different sexes
assess clinical signs
investigations via autopsy
Gain: MTD info, therapeutic index estimation, gender based differences, etc.

Question 3

Chronic systemic toxicity

Answer 3

14, 28-90 day or 9-12 months study
Cumulative doses, oral
2 species (1 non-rodent)
Full autopsy and clinical measures
Determine target organs affected

Question 4

Carcinogenic effects: in vitro testing

Answer 4

Ames test

• histidine, salmonella
• salmonella readily mutates if exposed to mutagen
• incubated in His- medium
• bacteria grows if it synthesises histidine (indicating presence of mutagen)
• incubated with liver extract (as liver metabolites may be carcinogenic)

Question 5

Carcinogenic effects: in vivo testing

Answer 5

Long term (2y study)
3 doses (high- MTD, med, low), oral
2 species, 1 nonrodent
Full autopsy at intervals
Tumour study

Question 6

Teratogenic effects

Answer 6

• fertility and general reproduction (male and female exposed prior to mating)
• teratogenicity test (chemical exposure at implantation through to end of organogenesis)
• perinatal study (last trimester through to lactation)

Question 7

Toxicogenomics

Answer 7

microarray analysis

indicates RNA levels to show up or down regulation of genes

Question 8

Limitations of toxicity testing

Answer 8

• Extrapolation from animals to humans is not completely reliable
• Rare adverse effects not likely to be detected

WHY? Not enough samples

rodents: predictive for 43 % of human toxicity
non-rodents: 63%
Rodent + non-rodent: 71%

Question 9

Phase I Clinical trials

Answer 9

Healthy volunteers , 50-100
safety, tolerability, ADME

1a) single dose
1b) repeated dose, 30-50 ppl

Question 10

Phase II

Answer 10

Patients with target condition

• efficacy and safety
• multiple dosing

Achieve primary end point

Question 11

Phase III

Answer 11

Confirmatory, efficacy, safety to support registration
long term tolerance
drug interactions

Question 12

Phase IV

Answer 12

Post-marketing surveillance

Adverse effects monitored