Final ProgramCPSA 2012
Transforming Drug Discovery & Development Through Innovation:
Past, Present and Future
October 1 - 4, 2012
Sheraton Bucks County Hotel
Langhorne, PA
Talk Synopsis
Tuesday, 3:15 pm - 4:45 pm
Session: Trends in Metabolite Profiling and Identification
What is the Purpose of Human ADME Studies?
Ronald White, XenoBiotic Laboratories
A study of the disposition of a new drug candidate in the human body is a universal requirement for marketing approval of small molecule drugs by health regulatory agencies around the world. ADME is an acronym for Absorption, Distribution, Metabolism and Excretion, and it would seem obvious, then, that the purpose of such a study would be to characterize the movement into and out of the body of drug-related materials, as well as the tissue distribution and routes of metabolic transformation within the body. However, it is not these parameters, per se, that represent the value of an ADME study. Rather, it is the interpretation of this information to explain the clinical actions of the drug that provides the real justification for the study. For instance, knowledge of the major metabolic pathways, should not be viewed as a mere compilation of metabolite structures, but as a central organizing principle to rationalize and anticipate such clinically important phenomena as drug-drug interactions, polymorphic pharmacokinetics, ethnic differences in pharmacokinetics, and production of active and/or toxic metabolites. Similarly, each component of the A. D. M. E. study is potentially rich in information that directly relates to the clinical performance of the drug. Historically, only was sought by regulators, and so a drug sponsor merely had to characterize the extent and route of excretion of drug-related materials, leading to the traditional name of "Mass Balance" which is still part of the jargon of the field. Radiolabeled drug was well-suited for this purpose, and it remains the core technology for the modern human ADME study. As new technologies became available, it became possible to ask more sophisticated experimental questions about the disposition of the drug, leading to the layering-on of A. D. and M. However, DM scientists and regulatory authorities have allowed the ADME study to become a check-box exercise rather than a true scientific investigation to reveal important aspects of the clinical actions of drugs. As we will discuss, the type of information derived from the typical human ADME study does not represent the most important information potentially available to fully characterize and explain the clinical profile of a new drug candidate. Thus, we will discuss improvements for the future ADME studies that are both desirable and technologically feasible today.
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