Simcyp® has been a joint venture between the University of Sheffield and a consortium of the world’s major pharmaceutical companies which attempts to integrate available in vitro data, generated during drug development, into user friendly software and companion database (the Simcyp Population-Based ADME Simulator). Applications of incorporating individual variability within diverse patient populations have been demonstrated using Simcyp in relation to predicting oral clearance [1], assessing inter-ethnic differences [2], estimating paediatric clearance [3] and estimating variation in drug absorption [4]. However, another less known function of the consortium has been to identify some complexities on a broad spectrum of DMPK issues and attempt to address them for the benefit of members.

The common PBPK models involving calculation of oral bioavailability are based on estimation of gut absorption (with or without components of gut first pass effect) and hepatic first pass effect. These models do not take into account that after the oral dosing a drug enters the systemic circulation in different states, that is, as free fraction, protein bound and partitioned (or not partitioned) into blood cells, and plasma lipids. Recently, Berezhkovskiy [5] has investigated the influence of drug kinetics in blood on the calculation of oral bioavailability in linear pharmacokinetics and indicated that the traditional equation may considerably overestimate the true value of availability. As part of this presentation it would be indicated that the ability to predict changes in fraction unbound is a key component of estimating hepatic first pass effect (Fh) from iv data. This becomes even more important when two drugs are given together as it becomes an essential component of the prediction of the extent of drug - drug interactions, especially if other mechanisms of interaction, such as changes in enzyme activity, are occurring simultaneously. 

[1] Howgate EM et al. Xenobiotica (in press).
[2] Inoue et al. Xenobiotica (in press)
[3] Johnson et al. Clin Pharmacokin (in press)
[4] Jamei et al. LogP 2004, Zurich, Switzerland
[5] Berezhkovskiy. Pharm Sci , 2006, 95:834–848