Week 6 Flashcards
(14 cards)
When to do in Vivo studies
after genotoxicity screening and ADME profiles. Compound should be chemically well characterised
In vivo Tests before phase I & II clinical trials
needs to extend as long as clinical trials will. Single dose tested for 2 weeks.
In vivo Tests before phase III clinical trials
Needs to extend past clinical trial duration.
2 weeks = 1 month rodents
1 month = 3 month rodents
3 month = 6 months rodents
> 3 months = 6 months rodents
Types of tox testing
- prenatal development
- first and second gen reproductive tox
- Toxicokinetics
- oral
- Reproductive/developmental
- repeat dose w repro/developmental
- neurotox
- Skin adsorption
- Skin sensistization
- Skin corrosion
- Phototox
- Skin irritation
- Carcinogenicity
- Chronic Tox
- Combined Carcino+chronic
- Genotox (MN, chromsomal aberrations)
Protocol requirements for GLP
Objective,
Identification of: test and control, sponsor, facility
Animal model justification and information (number, gender, species, age etc.)
Study design, control of bias
Animal husbandry info
Dose information
Methods of detection, statistical methods.
Records to be maintained
Selection Criteria for Species/Strain
- Requirements by regulatory agencies
- Metabolism of compound in a manner similar to humans
- Availability of historical control data
- Most sensitive species & strain
- Responsiveness of particular organs & tissues to specific toxicities
- Availability of species & strain
- Availability of appropriate animal housing & husbandry
- Experience of lab in using particular species & strain
Order of species:
- Mouse
- Rat
- Hamster
- Other rodent
- Rabbit
- Dog
- Non-human primate
- Other non-rodent mammal
- Non-mammals
Routes of admin. order:
- Intended human route
- Oral
- Intravenous
- Intramuscular
- Intraperitoneal
- Subcutaneous
- Inhalation
- Topical
- Other
Acute Toxicity study: (Single dose)
- Effects observed (usually in rodent & 2nd species) after a single dose for a 14 day period i.e. mortality, clinical signs (lethargy), body & organ weight changes, etc.
- Investigation of possible target organs by full autopsy (gross morphology)
Objectives: determine spectrum of toxicity, maximum tolerated dose, No observed adverse effect level, gender based reactions.
Single dose toxicity objectives
intermediate & delayed toxic effects
end points: clinical symptoms
Typical single-dose study design
Dosing: rats given a single dose of compound dissolved in sterile saline, control group injected saline (10 mL/kg)
Observations: rats observed frequently for signs of
intoxication during 1 st 4 hr after treatment, then at least once
daily for the 14 day observation period;
- individual body wt. recorded on days 0, 3, 7 & 14
- rats killed for macroscopic examination
Clinical symptoms: sluggishness, exophthalmus, convulsions, tremors, ataxia, paralysis, lachrymation, encrustations, piloerection, soiled fur, diarrhoea,
dyspnoea, emaciation, coma, hunching
Mortality: date & time found dead; body weight
Repeat-dose toxicity studies
Sub-acute (14 or 28 days), sub-chronic (90 days) & chronic (1-2 yrs*) studies (usually oral dosage used for longer exposures)
2 relevant species w both genders
Sub-Acute Repeat-Dose Toxicity
After successful Single-Dose Toxicity Testing
The information you want to get:
* An indication of effects of cumulative doses
* A symptom onset/resolution profile
* Local tolerance data
* Indications of toxicity to systems, organs &/or tissues likely to require further investigation in chronic exposure evaluations
Short-Term Repeat-Dose Study objectives
- adverse effects at dose low enough for animals to survive
- determine adverse effects
- dose response for repeated doses
- identify target organs
- differences in species sensitivity
Measure: food/water consumption, body weight, clinical signs, haematology
