Structural Identifiability and Indistinguishability Analyses of in vitro Pitavastatin Hepatic Uptake

Abstract

In this paper a review of the application of four different techniques (a version of the similarity transformation approach for autonomous uncontrolled systems, a non-differential input/output observable normal form approach, the characteristic set differential algebra and a recent algebraic input/output relationship approach) to determine the structural identifiability and indistinguishability of certain in vitro nonlinear pharmacokinetic models is provided. The Organic Anion Transporting Polypeptide (OATP) substrate, Pitavastatin, is used as a probe on freshly isolated animal and human hepatocytes. Candidate pharmacokinetic non-linear compartmental models have been derived to characterise the uptake process of Pitavastatin. As a prerequisite to parameter estimation, structural identifiability analyses are performed to establish that all unknown parameters can be identified from the experimental observations available. Furthermore, a structural indistinguishability analysis was performed to establish that all candidate models were structurally distinguishable for the given observations. This work is supported by the UK MRC Capacity Building Initiative and AstraZeneca.