Challenges in the Modelling of Bi-Directional Transport Experiments

With the advent of specialised user-friendly tools, physiologically-based pharmacokinetic models are no longer restricted to general purpose programming tools and scientists with modelling backgrounds. There is now an emerging need for similarly complex models to be applied to the analysis of data from in vitro PK and PD experiments. For example, the International Transporter Consortium has recently advocated the use of models which account for multiple physical spaces within drug transport experiments (Zamek-Glyszczynski et al., 2013). In the current study, apical and basolateral concentration data from bidirectional transport experiments were simultaneously modelled to gain system-independent and thus solely drug-dependent parameters for the active and passive processes of a compound with negligible paracellular permeability. Starting with a simple three-compartment model, the impact of incorporating specific system data, considering the multiple order of magnitude span of the data in the choice of parameter estimation method and accounting for procedural events such as replacement of media upon sampling was evaluated. Considering aspects such as these was found to be an important component in the modelling of these experiments and has emphasised a unique set of challenges when working with these data. Zamek-Gliszczynski MJ, Lee CA, Poirier A, Bentz J, Chu X, Ellens H, Ishikawa T, Jamei M, Kalvass JC, Nagar S, Pang KS, Korzekwa K, Swaan PW, Taub ME, Zhao P and Galetin A (2013) ITC recommendations for transporter kinetic parameter estimation and translational modeling of transport-mediated PK and DDIs in humans. Clin Pharmacol Ther 94(1) 64-79.