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 BV, Leiderdorp, The Netherlands; (2)Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands
Background and objectives: 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). To explore and quantify the influence of protein binding on the pharmacokinetics (PK) of solifenacin, we aimed to develop a mechanism-based PK model.
Methods: The "law of mass action" was used to describe the reversible solifenacin-AGP and solifenacin-albumin binding. The model also included binding of free solifenacin to a virtual binding compartment (VBC) positioned outside the plasma. In addition, a physiological expression was included into the model in order to relate the volume of distribution (Vd) to its physiological determinants. Total, free, AGP and albumin plasma concentration data from three clinical trials in healthy, elderly, renal and hepatic impaired subjects were used to parameterize the model with NONMEM VI. The model was externally validated on data from patients with OAB.
Results: A two-compartment model including protein binding best described the PK of total and free plasma concentrations of solifenacin. Based on individual plasma-AGP (range 26 - 181 mg/dL) and plasma-albumin (range 2.5 - 5.1 g/dL), free fraction was estimated as 0.0204 (range 0.00108 - 0.0411). The effect of free fraction on Vd (578 L; range 345 - 1151 L) and clearance (5.84 L/h; range 2.26 - 20.5 L/h) could also be quantified. Model evaluation by means of an internal and external visual predictive check showed satisfactory results.
Conclusions: A mechanism-based PK model was successfully developed allowing us to explore and quantify the influence of protein binding on the PK of solifenacin. This model constitutes a theoretical framework that could be applied to other drugs. In addition, it could be used to determine the influence of protein binding and body composition on the PK and pharmacodynamics of solifenacin.
