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WorksheetsDrug Discovery and Development Module 3: Pre Clinical Phase
Total questions: 45
Worksheet time: 24mins
Laboratory test of a new drug substance or medical devices, usually done on animal subjects
Preclinical Phase
Preclinical Trial
Nonclinical Trials
Clinical Phase
test performed outside of a living organism
(a)
test performed in living organisms
(a)
Lethal dose (LD50) - dose which kills 50% animals –Involves large numbers of animals, 4 days observation
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•Single high doses are given to small groups of animals
•Observed for mortality for 1-3 days
•Organ toxicity is examined by histopathology
Sub-chronic oral toxicity testing
Acute toxicity testing
Repeated dose toxicity testing
Chronic oral toxicity testing
•The test substance is administered orally for 90 days.
•The test substance is administered regularly at a specific time.
Sub-chronic oral toxicity testing
Acute toxicity testing
Repeated dose toxicity testing
Chronic oral toxicity testing
•Carried out for a minimum of 28 days
•The test substance is administered regularly at a specific time.
Sub-chronic oral toxicity testing
Acute toxicity testing
Repeated dose toxicity testing
Chronic oral toxicity testing
• The test compound is administered over more than 90 days, and the animals are observed periodically.
•Provides inferences about the long-term effect of a test substance
•Essential for new drug entities.
Sub-chronic oral toxicity testing
Acute toxicity testing
Repeated dose toxicity testing
Chronic oral toxicity testing
• Studies the effects of a test substance on the CNS
Carcinogenicity testing
Neurotoxicity studies
Repeated dose toxicity testing
Mutagenicity testing
•Observed for signs of toxicity and development of tumors.
•18 months for mice and hamsters; 24 months for rats
Carcinogenicity testing
Neurotoxicity studies
Genotoxicity testing
Mutagenicity testing
•Assess submicroscopic changes in the base sequence of DNA
Genotoxicity
Mutagenicity
Genotoxicity testing
Mutagenicity testing
permanent transmissible variations that can increase the frequency of mutations.
Genotoxicity
Mutagenicity
Genotoxicity testing
Mutagenicity testing
ability of harmful substances to damage genetic information
Genotoxicity
Mutagenicity
Genotoxicity testing
Mutagenicity testing
Used to identify gene mutations, chromosome changes, and alterations in the DNA sequencing
Genotoxicity
Developmental toxicity
Genotoxicity testing
embryotoxicity studies
At the end of the study or on the 21st day of the study, a caesarean section is performed and parameters such as fetal deformation and mortality are observed.
Genotoxicity
Mutagenicity
Genotoxicity testing
embryotoxicity studies
aka: embryotoxicity studies
Genotoxicity
Mutagenicity testing
Genotoxicity testing
Developmental toxicity
Rodents are preferred (M and F)
• Observed for 1 spermatogenic cycle and 2 estrous cycles
• Animals are allowed to mate and parturition is observed.
Two-generation reproduction toxicity testing
Toxicokinetics
One-generation reproduction toxicity testing
Deals with the kinetic patterns of higher doses of chemicals/toxins/xenobiotics
Two-generation reproduction toxicity testing
Toxicokinetics
One-generation reproduction toxicity testing
Skin irritation – reversible changes following the application of a test substance for up to 4 hours.
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Animal Used in Preclinical trials for:
Insulin injection
Metocurine injection
Tubocurarine
HPLC (rabbit)
Albino Rabbits
Male rat
Rabbits
Animal Used in Preclinical trials for:
Intracutaneous Test
Eye irritation Test
HPLC (rabbit)
Albino Rabbits
Male rat
Rabbits
Animal Used in Preclinical trials for:
Implantation Test
HPLC (rabbit)
Albino Rabbits
Male rat
Rabbits
Animal Used in Preclinical trials for:
Systemic injection test
Albino mice
Albino Rabbits
Male rat
Rabbits
Animal Used in Preclinical trials for:
Oxytocin injection
Sheep blood plasma
Chicken
Male rat
Rabbits
Animal Used in Preclinical trials for:
Vasopressin
Sheep blood plasma
Chicken
Male rat
Rabbits
Animal Used in Preclinical trials for:
Chorionic Gonadotropin
Spectrophotometer (Rachitic rat)
Female rat
Male rat
Abino Mice
Animal Used in Preclinical trials for:
Cod Liver oil
Spectrophotometer (Rachitic rat)
Female rat
Male rat
Abino Mice
Animal Used in Preclinical trials for:
Protamine sulfate
Heparin
Spectrophotometer (Rachitic rat)
Pigeon
Sheep blood plasma
Cat
Animal Used in Preclinical trials for:
Digitalis
Spectrophotometer (Rachitic rat)
Pigeon
Sheep blood plasma
Cat
Animal Used in Preclinical trials for:
Glucagon injection
Spectrophotometer (Rachitic rat)
Pigeon
Sheep blood plasma
Cat
Animal Used in Preclinical trials for:
Corticotropin Injection
Spectrophotometer (Rachitic rat)
Female rat
Male rat
Abino Mice
Serious eye damage – tissue damage in the eye, or serious physical decay of vision, following the application of a test substance to the front outer surface of the eye, which is fully reversible within 21 days.
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Skin sensitization: Local Lymph Node Assay (LLNA) » Most frequently used
In vivo
In vitro
Acute Eye Irritation / Corrosion
In vivo
In vitro
Fluorescein Leakage Test Method (FL)
In vivo
In vitro
Skin sensitization: the guinea pig maximization test (GPMT) and the Buehler test
In vivo
In vitro
Skin Sensitization: ARE-Nrf2 Luciferase Test Method
In vivo
In vitro
Bacterial reverse mutation test (Ames test)
In vivo
In vitro
mammalian cell gene mutation test
In vivo
In vitro
Acute Dermal Irritation / Corrosion
In vivo
In vitro
Skin Corrosion: Transcutaneous Electrical Resistance Test
In vivo
In vitro
agent that can cause an allergic response in animals or humans
Serious Eye Damage/Eye Irritation
Dose Descriptor for Eyes
Dose Descriptor for Skin
Sensitizer
No Observed Adverse Effect LeveL (NOAEL) cannot be obtained from skin/eye irritation tests due to study design
Serious Eye Damage/Eye Irritation
Dose Descriptor for Skin/Eye Irritation
Sensitizer
Draize tests on rabbits and guinea pigs for 14 days
Serious Eye Damage/Eye Irritation
Dose Descriptor for Skin/Eye Irritation
Sensitizer
Ethical Consideration in Animal Experimentation – 3R’s
Replacement
Reduction
Refinement
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