PI-023 - INCORPORATING HEPATIC TRANSPORTER ZONATION INTO PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELS: IMPLICATIONS FOR PRAVASTATIN DISPOSITION IN WHITE AND CHINESE POPULATIONS CONSIDERING OATP1B1 PHENOTYPES.

M. Hartauer¹, W. Murphy¹, K. Brouwer¹, S. Neuhoff²; ¹University of North Carolina Chapel Hill, Chapel Hill, NC, United States, ²Certara UK, Sheffield, UK.

Background: The cholesterol-lowering drug, pravastatin (PRV), is a substrate of several transporters (e.g., OATP1B1/3, MRP2/3). PRV’s pharmacodynamic (PD) target is located inside of hepatocytes. Therefore, PD response may be driven by unbound hepatocellular concentrations (Cu,IW), which can be predicted using PBPK models. Quantitative data on the zonation of hepatic transporters across the liver has been generated recently. In this study, a permeability-limited multicompartment liver model was used to evaluate the effect of quantitative transporter zonation on systemic and unbound hepatocellular PRV concentration predictions in White and Chinese populations.

Methods: A six-compartment liver PBPK model was used to simulate PRV systemic concentration-, unbound zonal hepatic extracellular water concentration (Cu,EW)- and Cu,IW-time profiles after single oral doses in White and Chinese healthy subjects with extensive, intermediate, or poor OATP1B1 phenotypes (ET, IT, PT, respectively; Simcyp V23). Model simulations were performed assuming uniform or quantitative (nonuniform) hepatic transporter zonation. A second PBPK model using these conditions was developed for PRV incorporating MRP3-mediated sinusoidal efflux.

Results: Systemic PRV AUC was 49% higher in Chinese compared to Whites, which was also simulated across different OATP1B1 phenotypes. In ET White and Chinese subjects, simulated systemic and Cu,EW PRV Cmax and AUC did not differ by more than 1% with uniform vs. nonuniform transporter conditions. However, pericentral (Zone 6) Cu,IW PRV Cmax and AUC were ~55% higher in nonuniform compared to uniform transporter conditions in both populations. In IT and PT Whites, Zone 6 Cu,IW PRV AUC was 11% and 19% higher, respectively, than ET Whites when using nonuniform transporter conditions. Compared to ET Chinese, Zone 6 Cu,IW PRV AUC was 2% higher in IT and 19% lower in PT Chinese. Incorporating MRP3 transport and re-optimizing the PRV model to fit clinical data did not change zonal Cu,IW PRV Cmax or AUC predictions by more than 3% in both populations.

Conclusion: This study highlights the importance of incorporating quantitative transporter zonation into PBPK models to assess the impact of ethnicity and OATP1B1 phenotypes on hepatocellular PRV disposition.