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Physiologicaly based pharmacokinetic modelling of transporters in drug discovery and development

3 September 2012  •  Author(s): Pradeep Sharma and Katherine Fenner, Global DMPK, AstraZeneca R&D

Physiologically based pharmacokinetic (PBPK) models describe the different compartments (tissues) in the body linked via arterial and venous blood flow (Figure 1). The volume of each tissue and blood flows are available from literature data1-5 and PBPK models have been developed for many species including rat, mouse, dog, pig and human2,6,7. PBPK models can be applied to many aspects of the drug develop ment continuum, from drug discovery8 and into development including use in regulatory responses9.

PBPK modelling is becoming a tool of choice in the pharmaceutical industry for the prediction of pharmacokinetic parameters, drugdrug interactions (DDI) and tissue distribution from in vitro data. PBPK modelling was able to become a mainstream tool in the pharma – ceutical industry with advances in in vitro metabolism techniques along with the ability to predict tissue distribution parameters or Kp values for a number of classes of compounds10-13. These models usually assume that the liver and kidney are the only organs where elimination occurs and that blood flow to these organs limits the excretion rate. Recently, with advances in in vitro techniques to study transporter proteins, the input of these data in PBPK models is becoming more commonplace.

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