|
|
|
|
|
|
|
the pharmacokineticist accepts the notion or not, the most important activity of that discipline during preclinical development is to support toxicology studies. This type of support, although not yet clearly understood and often poorly characterized, is critical to support safety prediction from animals to man. Nonclinical studies predict human safety better than they predict efficacy. |
|
|
|
|
|
|
|
|
Thus, many of the activities described in Table 1 should be deemphasized or dropped. Single-and multiple-dose pharmacokinetics and dose proportionality studies in animals may be of limited predictive value to humans and should be minimized. Autoradiography is not essential for every compound and should be restricted to those for whom information regarding tissue distribution of drug-related radioactivity is critical. Studies examining drug absorption in animals are an inefficient use of resources because of the generally poor predictability of these data to humans [18]. Similarly, extensive in vivo metabolite profiling in animals should become redundant as in vitro metabolism technology matures. Pharmacokinetic-pharmacodynamic interaction studies in animals may play a useful role for some compounds. However this is not universally the case. Even when good nonclinical pharmacodynamic data can be obtained, their relevance to the human clinical situation is uncertain. |
|
|
|
|
|
|
|
|
While pharmacokinetic studies need to be deemphasized, greater emphasis will continue to be placed on toxicokinetic studies. As discussed earlier, toxicokinetic studies and establishing toxicokinetic-toxicodynamic relationships will continue to play an increasingly important role in nonclinical drug development. More use will continue to be made of these relationships to assess drug exposure in experimental animals and to link this with projected clinical safety margin. The major limiting factor in the evolution of these disciplines is the poor characterization and human predictability of toxicological end-points. However, advances being made in the understanding of cellular pathophysiology and target organ susceptibility, together with increased knowledge of concentration-effect relationships, and also increased demand from regulatory agencies for such data to support drug safety claims, will continue to provide impetus for expansion of these activities [19]. It is unfortunate that any pharmacokinetics resources gained from downsizing nonclinical pharmacokinetic activity are likely to be lost, at least in part, due to increasing demands for toxicokinetic and toxicodynamic data. Some areas of pharmacokinetics and toxicokinetics involvement that should receive greater or less emphasis during preclinical discovery and development are summarized in Table 4. |
|
|
|
|
|
|
|
|
D. Clinical Pharmacology and Clinical Pharmacokinetic Studies |
|
|
|
|
|
|
|
|
The period during which a drug candidate is first administered to humans represents the first phase of a long and expensive clinical program, a great |
|
|
|
|
|