Mechanism-based pharmacokinetic modelling to describe the effect of protein binding on the pharmacok...
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Model structure

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Model structure

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

[email protected]

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


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