CPSA Shanghai 2011
Changing Paradigm in Drug Discovery & Development:
East Meets West
April 13 - 16, 2011
Renaissance Shanghai Pudong Hotel
Shanghai, China
Abstract
Friday PM - Parallel Session III
Application of PBPK and In Vitro Hepatocyte Models to Accurately Predict Human PK
Yurong Lai, Ph.D., Pfizer, Inc.
Prediction of hepatic clearance from a variety of in vitro systems has formed a cornerstone of the design and selection of small molecule drug candidates within the pharmaceutical industry. Past the decades, the kinetic parameters from in vitro models have been successfully applied to estimate the enzymatic metabolism in vivo when the absolute content of each P450 enzymes expressed in human liver is taken into account. Sandwich cultured hepatocytes (SCHH) have been used as a tool to characterize biliary secretion of drug candidates. This culture model offers the unique advantage of enabling transporters to remain in the correct vectorial orientation within an in vitro system, and allows for closer evaluation of the mechanism behind hepatobiliary secretion. However, the confidence in hepatic disposition mediated by drug transporters remains challenging. As conditions of hepatocyte culture could affect the transporter expressions, the modification might lead to the functional alternation and contribute the disconnection between in vitro and in vivo.
A PBPK model is a quantitative mathematical description of the physiological system and describes mathematically how the drug moves through the body. The disposition model is divided up into different compartments corresponding to the different tissues in the body which are linked together by the blood flow. Due to the complex nature of hepatic clearance prediction, we evaluated the possibility of utilizing SCHH to access the active processes of hepatic uptake and biliary excretion, and further for the prediction of in vivo clearance. In combination with PBPK modeling approaches, we demonstrate that in vitro/in vivo extrapolation of transporter mediated processes to predict plasma pharmacokinetics may be feasible with rigorous consideration of experimental methods and computer modeling implementation. In addition, the presentation will also discuss the major outstanding questions in terms of the prediction, such as tissue binding and scaling factors.