Lecture 7: Use of animal models in Pharmacology

Question 1

Identify the main reasons that makes animal experimentation necessary.

Answer 1

1. Molecular studies/studies with isolated tissues cannot predict the integrated response in the whole animal.
2. Finding new drugs is an increasingly costly exercise. Companies and institutions are not prepared to embark on a multi-million-dollar development program unless there is reliable evidence from animal studies.
3. Government regulatory bodies demand high standard to protect public and toxicity testing of new drugs in animals is required by law.

Question 2

Recognize the main factors that contributed to the Thalidomide tragedy.

Answer 2

• This happened because of inadequate animal testing. Was found to have ‘no effect’ on animals.
  -It was never tested on pregnant women.

-> It should not be used by people who are trying to conceive a child or by females who are breastfeeding/pregnant.

Question 3

Identify reasons for performing bioassays in humans.

Answer 3

1. The animal experiments do not predict human responses, or when the response is subjective and not measurable in animals.
2. Any drug that is intended for therapeutic use in humans has to be tested in human subjects first.

Question 4

Describe the rationale for the choice of administered doses in humans.

Answer 4

-Very difficult to extrapolate the first dose to be used in humans.
-The minimum effective dose is measured in animal species and then translated for humans by using the surface area of the animals.

1. If the test species is a rat, then 1/200 dose is used.
2. If it’s a dog 1/10 dose.
3. if nonhuman (monkey) or subhuman (orangutan or baboon) primate is used then the dose is 1/2.

Question 5

Describe the four main phases of the clinical development of drugs.

Answer 5

Phase 1. Clinical pharmacology (20-80 subjects)
- Healthy volunteers or volunteer patients, according to the class of drugs and safety.
- Pharmacokinetics (absorption, distribution, metabolism, excretion)
-Pharmacodynamics (biological effects), tolerance, safety, efficacy.

Phase 2. Clinical investigation (100-300 subjects)
-Patients - clinical setting
- Pharmacokinetics and pharmacodynamics, various doses, safety, efficacy.

Phase 3. Formal therapeutic trials (randomized controlled trials 250-1000+ subjects)
- Efficacy on substantial scale, safety, comparison with existing drug, statistical power.

Phase 4. Post-licensing studies (1000-10,000+ subjects)
- Surveillance for safety and efficacy, further formal therapeutic trials, especially comparison with other drugs.

Question 6

TOXICOLOGY

Answer 6

To see whether and how the drug causes injury (in vitro and in vivo tests)
-acute (single dose) toxicity
-subacute and chronic (repeated-dose)

Question 7

In vivo studies can yield to what insights

Answer 7

1-Reveal the unexpected (which can provide benefit)
2-Determine the therapeutic index =ED50(unwanted effect)/ED50 (wanted effect)
3-Assess relative importance of different pathways (ex. eicosanoid cascades)
4-Determine pharmacokinetics (ADME)
5. Asses safety and toxicology.