Can Population Modelling Principles be Used to Identify Key PBPK Parameters for Paediatric Clearance Predictions? An Innovative Application of Optimal Design Theory.

ABSTRACT:

Purpose

Physiologically-based pharmacokinetic (PBPK) models are essential in drug development, but require parameters that are not always obtainable. We developed a methodology to investigate the feasibility and requirements for precise and accurate estimation of PBPK parameters using population modelling of clinical data and illustrate this for two key PBPK parameters for hepatic metabolic clearance, namely whole liver unbound intrinsic clearance (CLint_,u,WL) and hepatic blood flow (Qh) in children.

Methods

First, structural identifiability was enabled through re-parametrization and the definition of essential trial design components. Subsequently, requirements for the trial components to yield precise estimation of the PBPK parameters and their inter-individual

SUBMITTER: Calvier EAM 

PROVIDER: S-EPMC6156772 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature