The interpretation of the results of all trials requires the close collaboration of
clinicians and statisticians. Reliable results are only obtained if at least the min-
imum number of patients for statistical viability are involved in the preliminary
trials.Itisoftendifficulttomeasurepreciselytheparameterchosenforassessment.
Consequently, results are usually quoted in terms of a probability coefficient, the
lower the value of this coefficient the more accurate the results. However, very
reliable results will only be obtained from clinical trials if large groups of patients
are tested. This is seldom feasible. Consequently, manufacturers and licencing
authorities usually settle for the best statistical compromise. Since some adverse
effects do not manifest themselves for years, it is necessary to constantly monitor
the drug (Phase IV trials) after it has been released for general use.
A more effective interpretation of pharmacological and toxicological data
may usually be made if the ADMEs of the drug and its metabolites are well
defined (see section 8.4). Tissue distribution data is usually obtained using single
dose studies but repeated dose studies should be undertaken when:
1. the tissuet1/2of the drug or metabolite is much larger than its plasmat1/2
value,
2. theCssof the drug or its metabolites is found to be very much higher than
that predicted from single dose studies,
3. the drug is targeted at a specific site and
4. particular types of tissue show unexpected lesions.
11.4 Drug metabolism and pharmacokinetics
Drug metabolism and pharmacokinetic (DMPK) studies are used to show how
the concentrations of the drug and its metabolites vary with the administered
dose of the drug and the time from administration. They are normally carried
out using suitable animal species and in humans in Phase I trials. The infor-
mation obtained from animal studies is used to determine safe dose levels for use
in the Phase I clinical trials in humans. However, the accuracy of the data
obtained from animal tests is limited, since it is obtained by extrapolation. In
addition, it is necessary to determine the dose that just saturates the absorption
and elimination processes so that the toxicological and pharmacological events
may be correctly interpreted.
234 DRUG DEVELOPMENT AND PRODUCTION