Subchronic toxicity studies, conducted in at least two animal species, usually
consist of daily administration of the drug for up to 90 days. Physical examina-
tions and laboratory tests are performed throughout the study and at the end of
the study to see what organs may have been adversely affected by the drug.
Chronic toxicity studies, also conducted in at least two species, usually last
the lifetime of the animal but the length of the study may depend on the intended
duration of drug administration to humans. Three dose levels are used, varying
from a nontoxic low-level dose to a dose that is higher than the expected thera-
peutic dose and is toxic when given over a long period of time. Physical exam-
inations and laboratory tests are performed to determine which organs are
affected and whether the drug has the potential to cause cancer (carcinogenic).
Animal studies enable scientists to develop a therapeutic index for the drug.
A therapeutic index is the ratio between the median lethal dose and the median
effective dose. It tells a practitioner the safe dose to give for the therapeutic
effect to be achieved.
Some drugs have a narrow margin of safety and require that the blood plasma
levels be frequently monitored to assure that the drug stays within the therapeu-
tic range. Drugs that have a wide margin of safety don’t require that the plasma
levels be monitored. Digitalis (digoxin) is an example of a drug that has a nar-
row margin of safety and requires frequent monitoring of plasma levels.
Scientists also learn how the drug is absorbed, distributed, metabolized, and
excreted once it is administered to the animals. This helps scientists predict how
the drug will react when administered to humans.
Tests are also conducted in laboratory test tubes that can determine the metab-
olism of the drug in humans, which may be different from animals. These are
calledin vitrostudies. Once animal studies are successfully completed, the drug
is ready for human trials during which human subjects are given the drug. There
are three phases of human trial.
PHASE I: INITIAL PHARMACOLOGICAL EVALUATION
In Phase I, drug trials, the drug is given to a small number of healthy volunteers
to determine safe dosage levels. The purpose is to document the dose level at
which signs of toxicity first appear in humans, determine a safe tolerated dose,
and determine the pharmacokinetics of the drug. Pharmacokinetics will be dis-
cussed in Chapter 2. Volunteerswho give consent to participate are monitored
closely during this phase. Permission must be obtained from the FDA to conduct
Phase I clinical trials.
CHAPTER 1 An Inside Look at Pharmacology^9