Quantitative evaluation of in-vivo function of drug transporters and metabolizing enzymes at therapeutic doses from microdose clinical study in humans based on in-vitro measurements of metabolism, transport and binding using PBPK modeling

In new drug development, binding affinities to the target molecule (related to pharmacodynamics), rates of metabolism and membrane permeabilities (related to pharmacokinetics) will be studied by in vitro experiments. However, prediction of human drug response from animal and in-vitro experiments is far from optimal, with most of drug candidates dropping out in human development. RIKEN, Japan's Institute of Physical and Chemical Research, has established Sugiyama Laboratory to promote the construction of an integrated support system for efficient drug discovery and development. In Sugiyama Laboratory mathematical models that incorporate parameters obtained from a variety of in vitro screening are being developed, and will be used for the quantitative simulation of pharmacokinetics and pharmacodynamics. In addition, the use of human microdose studies and PET molecular imaging enable real-time, safer, and less-invasive quantification of PET-probed drugs and drug candidates in target organs and will be useful for the optimization of the mathematical models.