PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of aapsjspringer.comThis journalToc AlertsSubmit OnlineOpen Choice
 
AAPS J. 2016 May; 18(3): 746–756.
Published online 2016 March 7. doi:  10.1208/s12248-016-9895-0
PMCID: PMC5256613

Does the Systemic Plasma Profile Inform the Liver Profile? Analysis Using a Physiologically Based Pharmacokinetic Model and Individual Compounds

Abstract

The physiologically based pharmacokinetic (PBPK) model for liver transporter substrates has been established previously and used for predicting drug–drug interactions (DDI) and for clinical practice guidance. So far, nearly all the published PBPK models for liver transporter substrates have one or more hepatic clearance processes (i.e., active uptake, passive diffusion, metabolism, and biliary excretion) estimated by fitting observed systemic data. The estimated hepatic clearance processes are then used to predict liver concentrations and DDI involving either systemic or liver concentration. However, the accuracy and precision of such predictions are unclear. In this study, we try to address this question by using the PBPK model to generate simulated compounds for which we know both systemic and liver profiles. We then developed an approach to assess the accuracy and precision of predicted liver concentration. With hepatic clearance processes estimated using plasma data, model predictions of liver are typically accurate (i.e., true value is bounded by predicted maximum and minimum); however, only for a few compounds are predictions also precise. The results of the current study indicate that extra attention is required when using the current PBPK approach to predict liver concentration and DDI for transporter substrates dependent upon liver concentrations.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-016-9895-0) contains supplementary material, which is available to authorized users.

KEY WORDS: identifiability analysis, liver transporter, physiologically based pharmacokinetic (PBPK) model

Articles from The AAPS Journal are provided here courtesy of American Association of Pharmaceutical Scientists