TOXIC STUDIES

K V GOPINATH M Pharm PhD,CPhTTirumala Tirupati Devasthanams

TIRUPATIe-mail:gopinath.karnam@gmail.com

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.

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.

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)

CLASSIFICATION CRITERIA FOR SUBSTANCES

Exposure Route Exposure Route 1 Category 1

Exposure Route Category 2

Exposure Route Category 3

Exposure Route Category 4

Exposure Route Category 5

Oral (mg/kg)

5 50 300 2000 5000

Dermal (mg/kg)

50 200 1000 2000

Gases (PPM)

100 500 2500 5000

VapoursMg/l

0.5 2 10 20

Dusts & Mists

0.05 0.5 1.0 5.0

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.

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.

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.

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.

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.