Model structure

1. Mechanism-based pharmacokinetic modelling to describe the effect of protein binding on the pharmacokinetics of solifenacinAshley Strougo1,2,, Walter Krauwinkel1, Meindert Danhof2, Jan Freijer11 Exploratory Development Department, Astellas Pharma Europe, The Netherlands; 2Division of Pharmacology, LACDR, Leiden University, The Netherlands ashley.strougo@eu.astellas.com Introduction  Solifenacin succinate is a muscarinic receptor antagonist used for the symptomatic treatment of overactive bladder (OAB).  The parent compound extensively binds to α1-acid glycoprotein (AGP). Aim Develop a mechanism-based model that considers plasma protein binding, plasma volume and body composition and holds improved properties for extrapolation and prediction. Data • Model structure • Law of mass action applied to describe the reversible solifenacin-AGP, solifenacin-albumin and solifenacin-VBC binding • VBC positioned outside of the plasma Table 1: Data overview Absorption compartment ka Central compartment AGP-Solifenacin Albumin-Solifenacin VBC-Solifenacin Q Peripheral compartment Solifenacinfree Total, free, AGP (range 30 - 166 mg/dL) and albumin (range 2.5 - 5.1 g/dL) concentration available; *Model validation Cl • Model equations • NONMEM VI and library ADVAN4 were used • Parameters were defined as follows: • Model results 4 • Visual Predictive Check Internal Figure 1: Relationship between free fraction and plasma proteins. Symbols: observed data; red line: population prediction; salmon shade: 90% confidence interval of the population prediction External • Conclusion • The developed mechanism-based PK model: • Adequately describes the PK of solifenacin in different sub-populations • Explains considerable part of the inter-individual variability • Constitutes a theoretical framework that could be also used to explore and quantify the effect of protein binding on the PK of other compounds • Holds much-improved properties for extrapolation and prediction by considering differences in body composition, plasma volume, AGP and albumin plasma concentrations Figure 2: Visual predictive check. Symbols: observed data; red line: population prediction; salmon shade: 90% confidence interval of the population prediction; dark grey shade: 90% of the population predicted based only on covariates; light grey shade: 90% of the population including random-effects References 1 Smulders et al.(2007),Pharmacol Sci 103: 67 - 74 2 Kuipers et al.(2006), Pharmacol Sci 102: 405 -412 3 Krauwinkel et al.(2005), Int J Pharmcol Ther 43:227-238 4 Wilkison et al. (1983), Drug Met Rewviews 14:427-465