R.H. Rose (1), S. Neuhoff (1), K. Abduljalil (1), M. Chetty (1), M. Jamei (1), A. Rostami-Hodjegan (1,2)
(1) Simcyp Ltd (a Certara company), Sheffield; (2) School of Pharmacy and Pharmaceutical Sciences, The University of Manchester; UK
Objectives: To develop a PBPK/PD model that links the hepato-cellular concentrations of rosuvastatin (RSTN), predicted by a permeability-limited liver model within a full PBPK model, to the rate of cholesterol synthesis over time and to use the model to estimate the impact of OATP1B1 c.521TT, TC and CC sequence variations on the response.
Methods: PK/PD of RSTN in the Healthy Volunteer population was constructed in the Simcyp Simulator (v12.2). Using clinically observed concentration-time data, the Simcyp Parameter Estimation module was used to obtain the uptake clearance of RSTN into the liver for OATP1B1 genotypes with c.521TT, TC and CC sequence variations [1]. The structural model for the effect of RSTN on cholesterol synthesis was coded using the Simcyp custom PD scripting facility and was based on the report by Aoyama et al., (2010) [2]. The parameters for baseline were kept as in the original publication. However, the drug effect (inhibition of mevalonic acid synthesis) in our model was driven by the unbound intracellular water concentration (CuIW) in liver (as opposed to plasma). Therefore, associated values were obtained by re-fitting the data in dominantly wild type OATP1B1 genotypes. Simulations were performed to predict the PD response for the three OATP1B1 genotypes.
Results: The model allowed adequate recovery of clinical PK [1] and PD [2] profiles. Simulations indicated that while the mean plasma AUC0-48h was increased by approximately 50% and 90% for the heterozygote and CC-homozygote genotypes relative to the wild type, the liver CuIW AUC was reduced by 6% and 9%, respectively. The corresponding mevalonic acid AUC relative to baseline was reduced by 2.5% and 5%, respectively.
Conclusions: While some studies have indicated an association between the OATP1B1 c.521T>C sequence variations and reduced therapeutic response to statins, others have failed to support this [3]. The PBPK/PD modelling approach used in this study suggests only a small contribution of the c.521T>C sequence variation on interindividual variability in cholesterol synthesis effect of RSTN. Linking the PD response to the concentration at the site of action predicted by a full PBPK model allowed better insight into the impact of transporter genotype on PD response. Models which mechanistically account for local PK variability improve understanding of the apparent observed PD variability and helps in dissecting out the true system mediated variations in response [4].
References:
[1] Pasanen et al. (2007) Clin Pharmacol Ther 82: 726-733
[2] Aoyama et al. (2010) Biol Pharm Bull 33: 1082-1087
[3] Niemi et al. (2011) Pharm Rev 63: 157-181
[4] Rostami-Hodjegan (2013) Clin Pharmacol Ther 93: 152
Reference: PAGE 22 (2013) Abstr 2757 [www.page-meeting.org/?abstract=2757]
Poster: Absorption and Physiology-Based PK