Pre-clinical
studies
Content
•
Stages
of preclinical studies
•
Pharmacodynamic
studies
•
Toxicity
studies
•
Assessment
of safety index
Intended Learning Outcomes
At the
end of this lecture, student will be able to
• Explain
the stages of preclinical studies
• Outline
pharmacodynamic studies
• Explain
toxicity studies
• Discuss
the assessment of safety index
Preclinical Studies
Stages
• Drug
discovery (2-5 Years)
• Preclinical
phase (1-2 Years)
• Clinical
trial phase (5-7 Years)
• Regulatory
approval (1-5 Years)
• Restricted
marketing – PSUR (4 Years)
• Free
Major Areas of Preclinical Studies
PD studies
• Therapeutic
use – studied in animals
• Pressure
changes, ECG, ionotropic, chronotropic, CO, TPR
• Promising
results: Cellular level – in vitro evidence for receptor activity
• Molecular
level: For affinity, selectivity – Membrane fractions of tissues/ organs/
cultured cells
• Graded/
quantal assay to find ED50
Toxicological Studies
• Acute
toxicity study
– To
find out LD50
– Atleast
2 animal species, 2 routes
– In
graded dose to many groups
·
Subacute toxicity study
– To
find out target organ for susceptible toxicity
– 2
animal species
– 3
doses
– At
maximum tolerated dose – 4 weeks to 3 months
• Chronic
toxicity study
– If
the drug is intended for chronic use
– 2
animal species
– 1-2
years duration
– Simultaneously
with clinical trials
• Special
toxicity
– Mandatory
– Data
on teratogenicity, mutagenicity, carcinogenicity
Special Toxicity Studies
a)
Effect
on reproductive performance
• Sexual
behavior, fertility, parturition, lactation
b)
Teratogenicity
• 2
animal species (Rat and Rabbit)
• To
study the effect of organogenesis
• Foetus
– examined for skeletal/ visceral abnormality
c)
Carcinogenicity
• Drug:
mutation, benign/ malignant tumor
• Low
predictive power from animal test
• Unknown
etiology of most spontaneous cancer
• Long
latent period
• 2
animal species
• Same
dose as chronic toxicity for 2 years
d) Mutagenicity
• Abnormalities
to genetic materials
• Permanent
change to the hereditary constitution
• Mutation
to reproductive cells: Defect in first generation progeny
d)
Local
toxicity
• Dermal
toxicity
• Dermal
phototoxicity
• Vaginal
toxicity
• Ocular
toxicity
• Inhalational
• Allergic
studies
• Rectal
inflammation test
PK Studies
• In
several species
• ADME
• Relative
BA after oral / Parenteral
• Elimination
t 1/2
Assessment of Safety index
• Toxicological
studies and PD data
• LD50
/ ED50
• Therapeutic
index
• Safety
factor
• Max.
tolerated dose, No AEL dose
• HED
Summary
• Pharmacodynamic
studies: Therapeutic use – studied in animals
• Toxicological
studies
– Acute
toxicity: Toxicity following single administration of high dose
– Chronic
toxicity: Toxicity following chronic administration
• PK
studies: ADME, Relative BA after oral / Parenteral
