DRUG SAFETY

EVALUATION
DRUG DISCOVERY AND DEVELOPMENT Group 2
Asaldo
Baluca
Bendebel
Capon
Castillo
OBJECTIVES:

1. Explain the significance of in vitro / in vivo toxicity

studies in establishing the safety of new drugs.

2. Describe the methods and principles underlying various

toxicological tests ( in vivo/ in vitro).

3. Discuss the ethical requirements in the conduct of

animal and human testing.

4. Describe the guidelines in the ethical conduct n the care

and use of animals and humans in drug testing.
What is Drug Safety Evaluation?

All medicinal products carry risks in addition to their possible benefits. For
developing a new medicine, a decision can only be made if both benefits & risks are
addressed. Risk associated with the drug is minimized when medicines of good
quality, safety & efficacy are used rationally by an informed health professional & by
patients. Guidelines were developed to monitor drugs, foods & environmental
contaminants for adverse reactions & toxicity. Pharmacovigilance helps in reducing
the risk of harm by ensuring use of good quality medicines approprietely.
In beginning, guidelines were restricted to local needs. In clinical trilas, critical
efficacy endpoints are identifies in advance & sample sizes are estimated for
assessment of effectiveness.

BENDEBEL
DRUG SAFETY EVALUATION (TOXICITY STUDIES)

INTRODUCTION
In biology, the term "in situ" means that the examination and
observation of a rare occurrence take place where it occurs. Subjects
are examined on position and are not moved to another or channel. An
example is an observation of dolphins at sea. they observed where
they are found and are not moved to an aquarium or other container
which is more convenient. In cell science, in situ can mean something
in between in vivo and in vitro.

BENDEBEL
 IT IS THE ANOTHER IS ANIMAL
IN VIVO EXPERIMENT OR
PRECISE CELLULAR
TESTING WHICH IS AN
EXPERIMENT THAT IS DONE
IN MEDICINE, CLINICAL TRIALS
OBSERVATIONS DONE AND ANIMAL TESTING ARE
CONDITIONS ARE IN ANIMALS USUALLY RATS,
ON THE LIVING PRESENTED IN THESE PERFORMED IN VIVO TO
BIRDS, FROGS, AND OTHER ANALYZE THE OVERALL
TISSUE OF THE STUDIES. ANIMALS WHERE THE EFFECTS OF THE EXPERIMENTS.
WHOLE LIVING DRUGS ARE DIRECTLY
ORGANISM IN A INJECTED INTO THE BODY.
CONTROLLED SO IN VIVO EXPERIMETNTS,
"IN VIVO" IS A ENVIRONMENT. CONDITIONS ARE NOT
ONE EXAMPLE IS A CLINICAL MANIPUALTED OR
LATIN WORD
TESTING OR A CLINICAL CONTROLLED.
WHICH MEANS TRIAL WHICH CAN BE
IN VIVO EXPERIMENTS, LIVING
"WITHIN THE CONTROLLED TESTING OF A
CELLS, OR ANIMAL MODELS ARE
IN VIVO EXPERIMENTS ARE NEW DRUG OR DEVICE ON
LIVING." DONE IN THE ORGANISM'S
USED. IN VIVO STUDIES ARE
HUMAN SUBJECTS. THE CRUCIAL FOR THE
NATURAL ENVIRONMENT SUBJECTS ARE GIVEN THE DEVELOPMENT OF MEDICAL
IT IS FOUND TO BE MORE
OR IN THE ORGANISM DRUGS AND ARE OBSERVED DEVICES, SURGICAL
SUITED ON EXPERIMENTS
ITSELF. FOR A CERTAIN PERIOD OF INSTRUMENTS, ROCEDURES AND
DONE ON ORGANISMS
TIME NOVEL THERAPEUTICS.
THAT ARE ALIVE

BENDEBEL
 IT IS THE EXPERIMENT MOST EXPERIMENTS IN MOST OF THE CELLULAR,

IN VITRO OR OBSERVATIONS DONE

ON THE TISSUE OUTSIDE
CELLULAR BIOLOGY ARE
DONE THROUGH IN VITRO
BIOCHEMICAL EXPERIMENTS
ARE CARRIED OUT IN VITRO
OF THE LIVING STUDIES AND ARE NOT IN THE LABS TO TEST.
ORGANISM IN A CONDUCTED IN THE
CONTROLLED ORGANISM'S NATURAL
ENVIRONMENT, USUALLY ENVIRONMENT. THIS
USING PETRI DISHES AND RESULTS IN THE LIMITED
TEST TUBES. SUCCESS OF THE
IN VITRO METHODS ARE
EXPERIMENTS IN
WIDELY USED IN THE
SIMULATING THE ACTUAL
PHARMACEUTICAL
"IN VIVO" IS A LATIN CONDITIONS INSIDE AN
INDUSTRY TO PRODUCE
WORD THAT MEANS ORGANISM AND MAKE ITS
THE TERM IN VITRO IS LARGE SCALE
"WITHIN THE GLASS." OUTCOME LESS PRECISE.
USED IN CELL BIOLOGY PHARMACEUTICALS
THEREFORE THE STUDIES
TO EXPLAIN THE USING
WHICH ARE DONE
TECHNIQUES WHICH ARE MICROORGANISMS DUE
OUTSIDE THE LIVING
PERFORMED ON A COMPARED TO IN VIVO TO ITS EASE OF
ORGANISM,INSIDE GLASS
CONTROLLED EXPERIMENTS, IT IS LESS PRODUCTION AND
(TEST TUBES OR
ENVIRONMENT OUTSIDE EPENSIVE AND PROVIDES ECONOMIC BENEFITS,.
PETRISHISHES) ARE
A LIVING CELL OR QUICKER RESULTS.
KNOWN AS IN VITRO
STUDIES. ORGANISM

BENDEBEL
"Methods and principles
underlying various
toxicological tests."

BALUCA
CURRENT METHODS: GENERAL
CONSIDERATIONS
Toxicity studies are required to assess potential hazards to humans through the acute,
subchronic, and chronic exposure of laboratory animals to pesticides. The more specific
types of toxicity that are determined include carcinogenicity; developmental (including
teratogenicity in offspring) and reproductive toxicity; mutagenicity; and neurotoxicity

Detailed information on the metabolism or biotransformation of the pesticide is also

obtained. Consideration is given to testing individual metabolites in animals, and in or on
pesticide-treated plants to which humans could exposed through their diet. The extent of
metabolite testing required depends on the level of potential toxicity and environmental
persistence of the metabolite. With the exception of the acute toxicity tests, most tests are
conducted to determine the nature of any toxicity that can be produced by repeatedly dosing
animals over an extended period. The results enable toxicologists to estimate the safety of a
material of humans BALUCA
Weil (1972) published the following set of guidelines, which reflected a
consensus among toxicologists. These should be considered before initiating
a toxicity test:

1.Use, wherever practical or 2. Where practical, use

possible, one or more species
that biologically handle the
material qualitatively and/or
quantitatively as similarly as
possible to man. For this,
metabolism, absorption,
excretion, storage and other
physiological effects might be
considered.
several dose levels on the
principle that all types of
toxicologic and
pharmacologic actions in man
and animals are dose-related.
The only exception to this
should be the use of a single,
maximum dosage level if the
material is relatively nontoxic.

BALUCA
Weil (1972) published the following set of guidelines, which reflected a
consensus among toxicologists. These should be considered before initiating
a toxicity test:

3. Effects produced at higher

4. Statistical tests for
dose levels (within the
significance are valid only on
practical limits discussed in 2)
the experimental units that
are useful for delineating the
have been mathematically
mechanism of action, but for
randomized among the dosed
any material effect, some dose
and concurrent control
level exists for man or animal
groups.
below which this adverse
effect will not appear.

BALUCA
Weil (1972) published the following set of guidelines, which reflected a
consensus among toxicologists. These should be considered before initiating
a toxicity test:

5. Effects obtained by one route of administration

to test animals are not a priori applicable to
effects by another route of administration to man.
The routes chosen for administration to test
animals should, therefore, be the same as those to
which man will be exposed. Thus, for example,
food additives for man should be tested by
admixture of the material in the diet of animals.

BALUCA
SUBCHRONIC TOXICITY STUDIES
Most subchronic toxicity studies monitor clinical or behavioral
(neurological) signs of toxicity, body weight, food consumption, eye
effects, certain plasma or serum and urine parameters, organ weights,
and gross and microscopic pathology. Clinical and behavioral signs of
toxicity are observed and recorded daily. They can consist of activity,
gait, excreta, hair coat, and feeding and drinking patterns. Body weight
and food consumption data are routinely recorded throughout the study
at intervals (usually weekly) determined by the length of the study.
Ophthalmoscopic examinations are conducted at the beginning of the
study and, typically, just before it terminates.
BALUCA
 CHRONIC TOXICITY STUDIES
Information derived from chronic studies is used to assess potential hazards resulting
from prolonged and repeated exposure to a pesticide over a large portion of the human
life span. These studies usually last 12 to 24 months. Of particular importance are long-
term carcinogenicity studies, the purpose of which is to observe the test animals for the
development of neoplastic lesions after a lifetime of exposure at dose levels up to and
including the MTD determined from subchronic testing.

The emphasis of the carcinogenicity study is the detection of tumors in animals. For
these studies, both concurrent and historical control data are used to evaluate the
relevance of tumors. Historical control data should be derived from studies in the same
species and strain and, preferably, in the same laboratory as used in the study under
consideration.
CAPON
DEVELOPMENTAL TOXICITY STUDIES

Developmental toxicity studies are designed to assess the potential of

developmental effects in offspring resulting from the mother's exposure to
the test substance during pregnancy. These effects include death of the
developing organism, structural abnormalities, altered growth, and functional
deficiencies. In addition to the classic teratology (now called developmental
toxicity) study, a postnatal study is required by the EPA on a case-by-case
basis. It is in this study that functional deficiencies are best studied.

CAPON
DEVELOPMENTAL TOXICITY STUDIES

The EPA prefers that the rat and the rabbit be used in these studies; however,
hamster and mouse are also acceptable. Doses should be administered over
the period of major organogenesis (major visceral and skeletal formation) in
the fetus. The maternal animals only are dosed in this study and only for
specified periods. When day 0 is the day that evidence of mating was
observed, the rat and mouse are dosed on days 6 through 15; the rabbit, days
6 through 18; and the hamster, days 6 through 14.

CAPON
THANK YOU
DRUG DISCOVERY AND DEVELOPMENT

Group 2
Asaldo
Baluca
Bendebel
Capon
Castillo