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Toxic studies
1. TOXIC STUDIES
K V GOPINATH M Pharm PhD,CPhT
Tirumala Tirupati Devasthanams
TIRUPATI
e-mail:gopinath.karnam@gmail.com
2. Definitions
Toxicity : Any toxic (adverse) effect that a chemical or physical
agent might produce within a living organism.
Toxicology
Types of Toxic Studies
Acute toxicity : It refers to those adverse effects occurring
following oral or dermal administration of a single dose of a
substance, or multiple doses given within 24 hours, or an inhalation
exposure of 4 hours.
Sub acute Toxicity: It resembles acute toxicity except that the
exposure duration is greater, from several days to one month.
Sub chronic toxicity: It is the toxic exposures repeated or spread
over an intermediate time range (1 – 3 months)
Chronic Toxicity: It is the exposures (either repeated or
continuous) over a long (greater than 3 months) period of time.
3. SINGLE DOSE ACUTE TOXICITY
TESTING FOR PHARMACEUTICALS
INTRODUCTION
Acute toxicity studies in animals are usually necessary for any
pharmaceutical intended for human use.
It is useful in choosing doses for repeat-dose studies, providing
preliminary identification of target organs of toxicity, and,
occasionally, revealing delayed toxicity.
Acute toxicity studies may also aid in the selection of starting doses
for Phase 1 human studies, and provide information relevant to acute
overdosing in humans.
DEFINITION
Acute toxicity is the toxicity produced by a pharmaceutical when it is
administered in one or more doses during a period not exceeding 24
hours.
4. TESTING PROCEDURES
The test compound should be administered to animals to identify
doses causing no adverse effect and doses causing major (life-
threatening) toxicity.
The use of vehicle control groups should be considered
Acute toxicity studies in animals should ordinarily be conducted
using two routes of drug administration: (1) The route intended for
human administration, and (2) intravenous administration, if feasible.
Studies should be conducted in at least two mammalian species
(Rodents and non rodents)
6. OBSERVATION
Animals should be observed for 14 days after pharmaceutical
administration. All mortalities, clinical signs, time of onset, duration,
should be recorded.
Also reversibility of toxicity should be recorded.
Gross necropsies should be performed on all animals, including those
sacrificed, moribund, found dead, or terminated at 14 days.
Clinical pathology and histopathology should be monitored at an
early time and at termination (i.e., ideally, for maximum effect and
recovery).
The toxicity studies should be designed to assess dose-response
relationships and pharmacokinetics to develop the lead compound.
7. CHRONIC TOXICITY STUDIES
It is the ability of the substance or mixture of substances to cause
harmful effects over an extended period, usually upon repeated and
continuous exposure.
The result of chronic toxicity study in animals should suggest signs
and symptoms of adverse reactions to look for in man.
8. PRINCIPLE OF TOXICITY STUDIES
PRINCIPLE OF TOXICITY STUDIES
- Standard operating procedures (SOP’s) and NIH guidelines
should be thoroughly followed for these studies.
- It should be performed by well trained and qualified staff. -
- These should comply with norms of good laboratory
practices. - The test substances and systems should be properly
characterized and standardized.
ANIMAL PROTECTION Studies should be designed so that the
maximum amount of information is obtained from the smallest
number of animals
To avoid causing excessive pain or tissue damage in the animals,
pharmaceuticals with irritant or corrosive characteristics should not
be administered in concentrations that produce severe toxicity solely
from local effects.
9. Proposals For Clinical Study
Certain basic studies should be considered mandatory when
examining drug action in vivo
1. Make an assessment of drug exposure in the animal, preferably by
measurement of plasma drug concentrations at several time
points, and after several different doses.
2. Perform a measurement of the degree of plasma protein binding
of the drug, ex vivo if possible, and if not, then in vitro. This is vital
if comparisons are to be made of a drug action in more than one
species.
3. Obtain knowledge on the metabolism of the drug and determine
whether active metabolites could be influencing the results being
obtained.
10. Proposals For Clinical Study
4. Ensure that the dose schedules to be used are relevant to the way
that the drug will be used in humans to allow translational value to
the clinic.
5. Consider whether there is a temporal mismatch between the
exposure information being gained and the outcome measure being
investigated because this might give insight into the mechanism of
action of the compound under investigation.
6. Consider the determinants of target engagement whenever the
information above has been gathered.
