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
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).
Develop a mechanism-based model that considers plasma protein binding, plasma volume and body composition and holds improved properties for extrapolation and prediction.
Table 1: Data overview
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
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
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