L. Gaohua (1), M. Chetty (1), M. Jamei (1), A. Rostami Hodjegan (1, 2)
(1) Simcyp Limited, Sheffield, UK; (2) University of Manchester, Manchester, UK.
Objectives: The recent success in application of systems approach in the area of predicting pharmacokinetics (PK) has led many to believe a similar strategy for the prediction of pharmacodynamic (PD) aspects should be adopted and popularised [1]. Although the fundamentals of mechanism-based PD (MBPD) are not new, integration of these into platforms with a user-friendly interface has not taken place up until now. The aim of this study is to assess the ability of the PD modules within the Simcyp Simulator V.11 to predict PK and PD profiles of nifedipine (NIF) in Japanese populations.
Methods: Prior in vitro metabolism and physicochemical parameters of NIF were collated from the literature. These drug-specific data, along with system-specific data, were used in a minimal physiologically-based pharmacokinetic (PBPK) model to predict NIF concentration time profile for a virtual Japanese population. Further, reported parameters in Shimada et al. [2] for empirical and operational transduction models of NIF binding to a stimulus response model, as well as the classical Hill function, were used to simulate the decrease in systolic blood pressure. The simulations, using the same PD models, were repeated in the North European Caucasian (NEC) population and the simulation results were compared against clinical data.
Results: PK and PD profiles were successfully simulated in both Japanese and NEC populations, producing results consistent with reported clinical studies [3, 4]. In particular, including an effect compartment in the PD module improved the prediction of PD profiles. Whilst all the models could describe the observed data, the operational transduction model could be considered a more mechanistic account of NIF pharmacological response. The difference between the prediction and observation in the PK/PD in different populations might be due to the differences in the system related parameters and clinical study settings which were not available to be incorporated into simulations.
Conclusions: Implemented PK/PD models within the Simcyp Simulator are able to simulate both the PK and PD profiles of NIF in Japanese and NEC populations. Further applications could be envisaged which are facilitated by the new PBPK/PD link models.
References:
[1] Atkinson & Lyster, Clin Pharmacol Ther (2010) 88: 3-6.
[2] Shimada et al., Biol Pharm Bul. (1996) 19: 430-437.
[3] Takekoshi et al., Jpn Circ J (1981) 45: 852-860.
[4] Hirasawa et al., Eur J Clin Pharmacol (1985) 28: 105-107.
Reference: PAGE 21 (2012) Abstr 2356 [www.page-meeting.org/?abstract=2356]
Poster: Model evaluation