The Drug development process - Pharmaceutical Biotechnology: Concepts and Aapplications - page 77

Table 4.2 The range of major tests undertaken on a potential new drug during preclinical trials.
The emphasis at this stage of the drug development process is upon assessing safety. Satisfactory
pharmacological, and particularly toxicological, results must be obtained before any regulatory authority
will permit commencement of human trials
Pharmacokinetic profi le
Pharmacodynamic profi le
Bioequivalence and bioavailability
Acute toxicity
Chronic toxicity
Reproductive toxicity and teratogenicity
Mutagenicity
Carcinogenicity
Immunotoxicity
Local tolerance
The results of such studies not only help to identify any toxic effects, but also point to the most
appropriate method of drug administration, as well as the most likely effective dosage regime to em-
ploy. Generally, ADME studies are undertaken in two species, usually rats and dogs, and studies are
repeated at various different dosage levels. All studies are undertaken in both males and females.
If initial clinical trials reveal differences in human versus animal model pharmacokinetic pro-
fi les, additional pharmacokinetic studies may be necessary using primates.
Pharmacodynamic studies deal more specifi cally with how the drug brings about its character-
istic effects. Emphasis in such studies is often placed upon how a drug interacts with a cell/organ
type, the effects and side effects it induces, and observed dose-response curves.
Bioavailability and bioequivalence are also usually assessed in animals. Such studies are under-
taken as part of pharmacokinetic and/or pharmacodynamic studies. Bioavailability relates to the
proportion of a drug that actually reaches its site of action after administration. As most biophar-
maceuticals are delivered parenterally (e.g. by injection), their bioavailability is virtually 100 per
cent. On the other hand, administration of biopharmaceuticals by mouth would, in most instances,
yield a bioavailability at or near 0 per cent. Bioavailability studies would be rendered more com-
plex if, for example, a therapeutic peptide was being administered intranasally.
Bioequivalence studies come into play if any change in product production/delivery systems
was being contemplated. These studies would seek to identify whether such modifi cations still
yield a product equivalent to the original one in terms of safety and effi cacy. Modifi cations could
include an altered formulation or method of administration, dosage regimes, etc.
4.12.1 Proteinpharmacokinetics
A prerequisite to pharmacokinetic/pharmacodynamic studies is the availability of a suffi ciently
selective and sensitive assay. The assay must be capable of detecting and accurately quantifying
the therapeutic protein in the presence of a complex soup of 'contaminant' molecules characteris-
tic of tissue extracts/body fl uids. As described in Chapter 7, specifi c proteins are usually detected
and quantifi ed either via immunoassay or bioassay. Additional analytical approaches occasionally
used include liquid chromatography (e.g. HPLC) or the use of radioactively labelled protein.