Physiologically Based Pharmacokinetics in Drug Development and

INTRODUCTION Impetus for the Workshop A 2-day workshop on "Physiologically Based Pharmacokinetics (PBPK) in Drug Development and Regulatory Science" came to a successful conclusion on May 30, 2002, in Washington, DC. More than 120 international participants from the environmental and predominantly pharmaceutical industries, Food and Drug Administration (FDA), and universities attended this workshop, organized by the Center for Drug Development Science, Georgetown University, Washington, DC. The first of its kind specifically devoted to the subject, this intensive workshop, comprising 7 plenary presentations and 10 breakout sessions addressed 2 major objectives: (1) to "define demonstrated and potential contributions of PBPK in drug development and regulatory science," and (2) to "assess current PBPK methodologies with the identification of their limitations and outstanding issues." This report summarizes the presentations and recommendations that emerged from the workshop, while providing key references, software, and PBPK data sources in the appendices. The first day was initially devoted to presentations setting the stage and providing demonstrated applications to date. This was followed by breakout sessions that considered further opportunities and limitations, and which extended into Day 2 to deal with developments in methodologies and tools. Although the primary emphasis was on pharmacokinetics, consideration was also given to its integration specifically with mechanism-based pharmacodynamics. Although certain physiological aspects of disposition of substances by organs within the body had received attention earlier, it was in 1937, with the seminal work of Teorell, that an integrated approach to whole body physiologically based modeling of pharmacokinetics received first serious attention. However, owing to the resultant mathematical and computational complexities and the lack of some basic physiological information at the time, whole body physiological based pharmacokinetics (PBPK) did not become of age until the 1960s, when, with the aid of the digital computer, modeling contributions from the chemical engineering community reawakened interest in this area. Since then, there have been numerous applications of the approach to a wide variety of chemical and drug substances, varying from small to large molecules, as well as investigations with environmental compounds. Compared, for example, to the sum of exponentials modeling, which is purely descriptive of the observed behavior of the substance under investigation, whole body PBPK modeling provides a mechanistic and more realistic description of the behavior of the substance in various tissues, with the intent of addressing such questions as: Why do we see the observed behavior? Can we explain differences among compounds? Can we better predict pharmacokinetics in human from in vitro and preclinical information and provide increasingly confident predictions of events occurring with drugs at target and other sites (which are rarely directly observable in humans), with age, in disease, and when co-administered with other drugs. When planning the workshop, the organizers were intrigued that whereas PBPK modeling has become relatively well accepted in the field of risk assessment by the chemical industry and environmental protection agencies, its pharmaceutical application has remained relatively academic to date with little obvious general appliCorresponding Author: Malcolm Rowland, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK. Tel: +44 161 275 2348. Fax: +44 161 273 8196. Email: [email protected].