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 pharmacological efficacy of pharmaceutical agents. In recent years, the importance of ADME studies in toxicology also has become increasingly apparent. In realization of the importance of ADME studies, regulatory agencies have established guidelines governing the conduct of these studies. To be of maximum utility, it is desirable that ADME and pharmacokinetic studies be closely integrated with the toxicity testing protocol. However, in many instances this is not the case, which results in ADME and pharmacokinetic studies that are often chronologically and philosophically remote from the toxicity testing protocols. An inevitable consequence of this approach is that it frequently leads to the generation of ADME data that are of limited use in the process of toxicity evaluation and risk assessment. Recently, there has been increased focus on developing testing strategies that would result in the development 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 tiered approach is generating ADME data at an earlier stage during the toxicity testing of a chemical. This could be effected by acceptance of the concept of a minimum experimental data set for a chemical. This minimum data set could be conducted in a timely and economic manner and would develop data addressing three fundamental questions: Is the chemical absorbed? Is the chemical metabolized? Does the chemical persist? The data generated under a minimum data set scenario would not be designed to provide sufficient information for utility in risk evaluation. However, it would provide important information at a much earlier stage of toxicity testing than currently generated under existing testing strategies. Such information would be of importance in the design of toxicity testing studies. Additional ADME and pharmacokinetic information 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 particular toxicity or risk-evaluation end point (e.g., target organ, species extrapolation, route evaluation, etc.). The specifics of the experimental aspects of the design of ADME and phar