Overcoming the shortcomings of the extended-clearance concept: a framework for developing a physiologically-based pharmacokinetic (PBPK) model to select drug candidates involving transporter-mediated clearance

ABSTRACT

Introduction:Human pharmacokinetic (PK) prediction can be a significant challenge to drug candidates undergoing transporter-mediated clearance, when only animal data and in vitro human parameters are available in the drug discovery stage.

Areas covered:The extended clearance concept (ECC) that incorporates the processes of hepatic uptake, passive diffusion, metabolism and biliary secretion has been adapted to determine the rate-determining process of hepatic clearance and drug-drug interactions (DDIs). However, since the ECC is derived from the well-stirred model and does not consider the liver as a drug distribution organ to reflect the time-dependent variation of drug concentrations between the liver and plasma, it can be misused for compound selection in drug discovery.

Expert opinion:The PBPK model consists of a set of differential equations of drug mass balance, and can overcome the shortcomings of the ECC in predicting human PK. The predictability, relevance and reliability of the model and the scaling factors for IVIVE must be validated using either the measured liver concentrations or DDI data with known transporter inhibitors, or both, in monkeys. A human PBPK model that incorporates in vitro human data and SFs obtained from the validated monkey PBPK model can be used for compound selection in the drug discovery phase.

KEYWORDS:

• Physiologically-based pharmacokinetics model
• transporter mediated clearance
• extended clearance concept
• human pharmacokinetics prediction
• drug discovery

Article highlights

• The extended clearance concept (ECC) that incorporates the processes of hepatic transport, metabolism and/or biliary excretion is a simplified method to determine overall clearance and drug-drug interactions (DDIs) for drugs that undergo transporter-mediated clearance

• However, the ECC does not denote time-dependent changes of drug concentrations between the liver and plasma and can be misused in compound selection in the drug discovery phase.

• Therefore, a physiologically based pharmacokinetics (PBPK) model developed and validated in preclinical animals is necessitated for scaling factors (SFs); The SFs can then be incorporated in a human PBPK model for prospective prediction of human PK profiles using in vitro human data, to select the drug candidates undergoing transporter-mediated clearance

• Additionally, current efforts to optimize the assay conditions and the model fitting to in vivo animal PK data can be instrumental in obtaining compound-dependent empirical SFs for the improvement of prospective human PK prediction

This box summarizes key points contained in the article.

Declaration of interest

Both authors disclose being employees of Gilead Science Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was sponsored by Gilead Sciences Inc.