International Workshop on Uncertainty and Variability in Physiologically Based Pharmacokinetic (PBPK) Models

Additional Support

CIIT Centers for Health Research (CIIT)
L'Institut National de l'environnement industriel et des risques (INERIS)
Miami University
Summit Toxicology
U.K. Health and Safety Executive, Health and Safety Laboratory (HSL)

Organizing Committee

Weihsueh Chiu (chair), EPA/NCEA
Woodrow Setzer (co-chair), EPA/NCCT
John Bailer, Miami University
Hugh Barton, EPA/NCCT
Frédéric Bois, INERIS
Harvey Clewell, CIIT
Hisham El-Masri, EPA/NHEERL
George Loizou, HSL
Christopher Portier, NIEHS
Martin Spendiff, HSL
Sean Hays, Summit Toxicology

Summary

Risk assessments for chemicals increasingly utilize pharmacokinetic models, particularly physiologically based pharmacokinetic (PBPK) models. Characterizing the uncertainty in PBPK model parameterization and estimation of dose metrics for use in risk assessment is essential. In addition, human variability is an important factor to be characterized to appropriately describe human populations. The purpose of this workshop is to review and promote the appropriate application of methods for statistical characterization of PBPK models and the characterization of uncertainty and human variability through a cross-disciplinary exchange of experience and ideas among laboratory scientists, PBPK modelers, statisticians, and others with expertise in applied mathematics, biology, and pharmacokinetic analyses.

Introduction

As physiologically based pharmacokinetic (PBPK) models have become increasingly available for environmental chemicals and pharmaceuticals, there is an ongoing shift from the early model development efforts focused on demonstrating their feasibility and utility, to a recognition of the need for more formal and rigorous characterization of model inputs and outputs critical in their applications in risk or safety assessments. Areas for better characterization include:

Estimation of parameter values from in vivo and/or from in vitro data
Evaluation of alternative model structures
Assessment of uncertainty in model outputs
Characterization of human variability and its uncertainty

Recent efforts have used of a number of quantitative and statistical tools to better characterize the uncertainty and variability in pharmacokinetic analyses, including:

Sensitivity analyses
Monte Carlo simulation
Non-linear mixed effects modeling
Markov chain Monte Carlo (for Bayesian analyses)

However, to date, there has been no broad review or discussion of the many methodological and implementation issues uniquely posed by the application of statistical methods to PBPK model-based pharmacokinetic analyses.

Purpose and Goals

The purpose of this international workshop is to promote the appropriate application of methods for statistical characterization of PBPK models and the characterization of uncertainty and human variability through a cross-disciplinary exchange of experience and ideas among laboratory scientists, PBPK modelers, statisticians, and others with expertise in applied mathematics, biology, and pharmacokinetic analyses. To achieve its goal, this workshop will:

Review and assess the status of existing methodologies for characterizing uncertainty and variability in PBPK models.
Identify applications for which appropriate methodologies can be readily implemented given currently available data, information, and resources.
Propose ways to improve/expand the implementation of these methods (including software and training).
Identify key research priorities and/or data needs
Make available the findings of the workshop through workshop proceeding and a series of publications in the peer-reviewed literature.

Premeeting Draft White Papers

The following premeeting draft white papers are available:

Background Paper for Breakout Group I: Model Specification (PDF, 30 pp., 237 KB)
Breakout Group II: Introduction to Statistical Population Modeling and Analysis for Pharmacokinetic Data (PDF, 89 pp., 389 KB)
Discussion Paper for Breakout Session III: State of the Art in Issues of Uncertainty and Variability for PBPK Model Applications (PDF, 20 pp., 93 KB)