PWI-005 - APPLICATION OF A PERMEABILITY-LIMITED MULTI-COMPARTMENT LIVER MODEL TO INVESTIGATE RIFAMPICIN-MEDIATED ZONAL INDUCTION OF HEPATIC OATP1B1 IN A PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) FRAMEWORK.

M. Hartauer¹, W. Murphy¹, K. Brouwer¹, R. Southall², S. Neuhoff²; ¹University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, ²Certara UK Ltd. (Simcyp division), Sheffield, United Kingdom.

Background: Reduced exposure of repaglinide (RPG), organic anion transporting polypeptide 1B1 (OATP1B1) substrate, was reported following multiple-dose rifampicin (RIF) exposure. OATP1B1 induction is one possible mechanism responsible for this observation. Non-uniform regional distribution may impact induction of OATP1B1, which could explain contradictory observations reported in the literature. This was evaluated using a multi-compartment liver model within a PBPK framework in combination with OATP1B1 hepatic zonal distribution data.

Methods: Transporter induction was described by adjusting a previously developed turnover model, where the first-order degradation rate constant represents turnover of hepatic OATP1B1. Regional hepatic distribution data for OATP1B1 generated from immunofluorescent imaging was incorporated into a permeability-limited six-compartment liver model that was used to describe the PK of RIF and RPG. OATP1B1 intrinsic clearance was optimized in the RPG compound file and verified against observed data. The Simcyp Simulator (v21) was used to simulate RPG and RIF plasma concentration-time profiles after oral dosing regimens based on 4 independent clinical drug-drug interaction (DDI) studies. (1-3)

Results: The predicted/observed area under the curve (AUC) ratios for the 4 clinical DDI studies were 0.90, 1.63, 1.37, and 0.47, and the predicted/observed maximum plasma concentration (Cmax) ratios were 1.14, 0.93, 1.32 and 0.44, respectively.

Conclusion: Using a multi-compartment liver model, OATP1B1 zonal induction was evaluated as a mechanism of interaction between RIF and RPG. The developed PBPK model reasonably recovered observed data from 3 of the 4 clinical studies, supporting the hypothesis that a zonal induction pattern may occur for non-uniformly distributed hepatic transporters.

1. Bidstrup, T.B., et al. Rifampicin seems to act as both an inducer and an inhibitor of the metabolism of repaglinide. Eur. J. Clin. Pharmacol, 2004. 60(2): p. 109-14.
2. Hatorp, V., K.T. Hansen, and M.S. Thomsen. Influence of drugs interacting with CYP3A4 on the pharmacokinetics, pharmacodynamics, and safety of the prandial glucose regulator repaglinide. J. Clin. Pharmacol, 2003. 43(6): p. 649-60.
3. Niemi, M., et al. Rifampin decreases the plasma concentrations and effects of repaglinide. Clin. Pharm. & Ther., 2000. 68(5): p. 495-500.