A TIERED APPROACH TO PHARMACOKINETIC STUDIES

Studies of absorption, distribution, metabolism and elimination (ADME) have long been recognized as important in the evaluation of the pharm acological efficacy of pharmaceutical agents. in recent years, the imp ortance of ADME studies in toxicology also has become increasingly app arent, Tn realization of the importance of ADME studies, regulatory ag encies have established guidelines governing the conduct of these stud ies. To be of maximum utility. it is desirable that ADME and pharmacok inetic studies be closely integrated with the toxicity testing protoco l. However, in many instances this is not the case, which results in A DME and pharmacokinetic studies that are often chronologically and phi losophically remote from the toxicity testing protocols. An inevitable consequence of this approach is that it frequently leads to the gener ation of ADME data that are of limited use in the process of toxicity evaluation and risk assessment. Recently, there has been increased foc us on developing testing strategies that would result in the developme nt of ADME data with greater application to toxicity testing and risk assessment. An example of such an approach is the concept of a tiered approach to the conduct of ADME studies. An important aspect of the ti ered approach is generating ADME data at an earlier stage during the t oxicity testing of a chemical. This could be effected by acceptance of the concept of a minimum experimental data set for a chemical. This m inimum data set could be conducted in a timely and economic manner and would develop data addressing three fundamental questions: Is the che mical absorbed! Is the chemical metabolized! Does the chemical persist ! The data generated under a minimum data set scenario would not be de signed to provide sufficient information for utility in risk evaluatio n. However, it would provide important information at a much earlier s tage of toxicity testing than currently generated under existing testi ng strategies. Such information would be of importance in the design o f toxicity testing studies. Additional ADME and pharmacokinetic inform ation could then be conducted when a specific concern (e.g., toxicity) becomes apparent The advantage of this approach is that it allows the design of these additional follow-up studies to be tailored to the pa rticular toxicity or risk-evaluation end point (e.g., target organ, sp ecies extrapolation, route evaluation, etc.). The specifics of the exp erimental aspects of the design of ADME and pharmacokinetics studies a re discussed. In this development of alternate, and more efficient pro cedures, for the conduct of metabolism studies, ii has become apparent that the potential use of ADME data obtained under studies designated by the regulatory guidelines is often of little use in addressing the major concerns of risk assessment (i.e., species, dose, and route ext rapolation). In considering alternate approaches it has become apparen t that increased use of dosimetry models such as physiologically based pharmacokinetic models could have significant utility in improving th e risk assessment procedure. In recent years there has been growing su pport for the pharmacokinetic modeling approaches and, in particular, physiologically based pharmacokinetic (PBPK) models have been increasi ngly used in risk assessment by providing a unified description of the dynamics of chemicals and their metabolites in the blood. specific ti ssues and excreta, in addition to providing a dosimetric of the relati onship between the exposed concentration and tissue dose, these models can also be linked to so-called biologically based dose-response mode ls. These latter models are being developed to incorporate information on our understanding of toxicological mechanisms, Such models, in con junction with PBPK models provide an improved biological basis for exa mining the relationship between chemical exposure and effect. The adve nt of these models heralds the prospect of reducing the uncertainty in the risk assessment process.