Shinji Shimizu (1), Francisco Bellanti (1), Meindert Danhof (1), Elizabeth CM de Lange(1)
(1) Division of Pharmacology LACDR, Leiden University, the Netherlands
Objectives: Prediction of exposure level in the central nervous system (CNS) is critical during the development of CNS-targeted and non-targeted drugs[1, 2]. In fact, a number of approaches have been proposed to estimate CNS exposure, such as in vitro cell-line system, determination of concentration ratio of brain to plasma at steady state. However, in terms of translation from in vitro to in vivo or animal to human, the information on those preclinical data still remains to be fully interpreted. Recently, much attention has been drawn to physiologically-based pharmacokinetic (PBPK) modeling since this approach can potentially simulate drug concentrations in human tissues based on in vitro experimental data, in vivo animal PK data, or combination of them, in a mechanistic way[1, 2, 3]. The objective of this study is to develop a PBPK model to describe CNS drug distribution of risperidone and its active metabolite, paliperidone. In addition, an impact of P-gp functioning on the CNS entry of those drugs is assessed[4].
Methods: In our in vivo experiment, the microdialysis rat model was used to provide serial samples of plasma, brain extracellular fluid (ECF), and cerebrospinal fluid (CSF). Rats received risperidone or paliperidone intravenously after pretreatment of P-gp inhibitor, tariquidar (TQ). NONMEM analysis was carried out in a stepwise approach. As a first step, plasma PK model was developed for both compounds. As a second step, resulting plasma PK parameters were fixed and then used for the development of CNS distribution model. Physiological parameters, such as flow of ECF and CSF, and volume of each CNS site, were used to construct the CNS model.
Results: In visual predictive check (VPC), the proposed model well described the observed PK profile in plasma and CNS for both risperidone and paliperidone. Additionally, differences in PK between with and without TQ treatment were nicely captured.
Conclusions: The proposed PBPK model together with the microdialysis technique allowed us to describe CNS distribution as well as to quantify P-gp clearance for both risperidone and paliperidone in rats.
Reference: PAGE 23 () Abstr 3055 [www.page-meeting.org/?abstract=3055]
Poster: Drug/Disease modeling - CNS