Drug toxicity types
- Systemic toxicity (acute/ chronic)
- Carcinogenic effects
- Teratogenic effects/ reproductive toxicity
Acute systemic toxicity
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.
Chronic systemic toxicity
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
Carcinogenic effects: in vitro testing
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)
Carcinogenic effects: in vivo testing
Long term (2y study) 3 doses (high- MTD, med, low), oral 2 species, 1 nonrodent Full autopsy at intervals Tumour study
Teratogenic effects
- 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)
Toxicogenomics
microarray analysis
indicates RNA levels to show up or down regulation of genes
Limitations of toxicity testing
- 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%
Phase I Clinical trials
Healthy volunteers , 50-100
safety, tolerability, ADME
1a) single dose
1b) repeated dose, 30-50 ppl
Phase II
Patients with target condition
- efficacy and safety
- multiple dosing
Achieve primary end point
Phase III
Confirmatory, efficacy, safety to support registration
long term tolerance
drug interactions
Phase IV
Post-marketing surveillance
Adverse effects monitored
