1. 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 Visual Predictive Check Model equations  NONMEM VI and library ADVAN4 were used  Parameters were defined as follows: Data Mechanism-based pharmacokinetic modelling to describe the effect of protein binding on the pharmacokinetics of solifenacin Mechanism-based pharmacokinetic modelling to describe the effect of protein binding on the pharmacokinetics of solifenacin Ashley Strougo 1,2, , Walter Krauwinkel 1, Meindert Danhof 2, Jan Freijer 1 1 Exploratory Development Department, Astellas Pharma Europe, The Netherlands; 2 Division of Pharmacology, LACDR, Leiden University, The Netherlands  ashley.strougo@eu.astellas.com Model results 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. Absorption compartment ka Q Central compartment AGP-Solifenacin Cl VBC-Solifenacin Solifenacin free Peripheral compartment Study number Population Treatment schedule Dosage No. of subjects 21 1 Healthy & renal disease Single dose10mg24 26 2 Healthy & hepatic Impairment Single dose10mg16 29 3 Young & elderly14 days per period 5 mg;10 mg47 52*Patients OABMultiple doses 3 mg; 6 mg; 9 mg 628 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 Total, free, AGP (range 30 - 166 mg/dL) and albumin (range 2.5 - 5.1 g/dL) concentration available; *Model validation 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 Table 1: Data overview 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 4 Derived parameters Median (range) V central /F(L)271 (67.5 - 896) V peripheral /F (L)306 (149 – 1260) V ss /F (L)578 (345 – 1151) CL/F (L/h) 5.84 ( 2.26 - 20.5) Q/F (L/h)49.1 ( 26.1 - 99.2) f plasma 0.0204 (0.0108 – 0.0411) n AGP k AGP (nmol/L)504 (365 – 813) n Alb k Alb (nmol/L)3.93e+5 (2.84e+5 – 6.34e+5) Estimated parameters Value (CV %) Ka (/h)0.244 (10.0) CL Intrinsic (L/h)305 (5.97) Q intrinsic (L/h)2411 (15.0) VBC (µmol)4228 (13.0) f tissue 0.00129 (4.57) k AGP (nmol/L)1604 (18.2) k Albumin (nmol/L)1. 25e+6 (40.4) 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 External Internal Albumin-Solifenacin