(T1030-10-69) Evaluating the Relative Contribution of OATP2B1 Transporter on Rosuvastatin Pharmacokinetic Drug-Drug Interactions Using Mechanistic and Physiologically Based Pharmacokinetic Modeling

Purpose: Organic anion‐transporting polypeptide (OATP) 2B1 is well-known for differential expression in various organs such as the liver, intestine, lung, brain, and placenta. To date, OATP2B1 has been identified for its potential involvement in clinical drug-drug interactions with statins, taxols, and fexofenadine. However, relative to other OATPs, OATP2B1 still has a tagline as an “under-rated” transporter due to its limited substrate of choice and expression pattern. Rosuvastatin has been reported to be a substrate of multiple uptake and efflux transporters including OATP2B1. Notwithstanding, most of the studies on rosuvastatin were focused on OATP1B1/1B3 and breast cancer resistant protein (BCRP) transporters, with very few examples suggesting OATP2B1 as a possible contributing mechanism. Moreover, none of these studies explored the relative contribution of the low affinity/capacity transporter OATP2B1 compared to other high affinity/capacity transporters (OATP1B1/1B3) and particularly tissue-specific exposure. Our primary purpose was to investigate individual contribution of the OATP2B1 on rosuvastatin uptake and tissue specific disposition at clinical level with a secondary objective of a prospective drug-drug interactions with erlotinib.

Methods: We conducted in vitro cellular uptake studies using a recombinant human embryonic kidney cell lines overexpressing OATP2B1 and the intracellular uptake was quantified using LC-MS/MS system (Waters, Milford, MA, USA) coupled to a Triple Quad™ 6500+ mass spectrometer (AB Sciex). In addition, in vitro DDI studies were then conducted using a potent OATP2B1 inhibitor (Erlotinib). To extend our in vitro findings towards clinical translation, we predicted clinical DDI potential following FDA guidance. Finally, we developed a PBPK model using Simcyp (version 21.0) for 10mg rosuvastatin and 150mg single dose erlotinib to predict clinical DDI and tissue exposure among built-in healthy human subjects for a co-dosing trial design.

Results: Rosuvastatin demonstrates low affinity uptake by OATP2B1 (km=12.6 µM) in recombinant HEK-2B1 cells. OATP2B1-mediated rosuvastatin uptake was significantly inhibited by erlotinib in the absence (IC₅₀ = 0.07 uM) and presence (IC₅₀ = 0.23 uM) of 4%BSA. The DDI indexes for erlotinib were found to be 4.6 (C_max,u/IC₅₀) and 13.2 (R=1 + (C_{max,u, portal}/IC₅₀)) versus 1.4 and 4.7, respectively, in the presence of 4% BSA in vitro. The predicted PK from rosuvastatin and erlotinib PBPK models were then validated with clinically observed data (rosuvastatin AUCR: 1.2 and C_max 1.4; erlotinib AUCR: 1.2 and C_max 0.9). The DDI model predicted 76 and 60% reduction in AUC and fraction absorbed (fa) of rosuvastatin when co-administered with erlotinib. Our DDI-PBPK model also predicted about 66% reduction in portal vein concentrations and 60% reduction in total brain exposure of rosuvastatin. Further a PBPK model lacking OATP2B1 function predicted 90% reduction in brain exposure, suggesting a significant contribution of OATP2B1-mediated rosuvastatin uptake in the brain. Overall, in vitro to in vivo extrapolation by static mechanistic and PBPK modeling shows consistent drug-drug interactions predictions between rosuvastatin and erlotinib.

Conclusion: To our knowledge, this is the first study showing that despite a relatively lower contribution (ft_OATP2B1, _liver =10%), rosuvastatin local concentration (i.e., gut and brain) could be altered significantly by OATP2B1. A prospective drug-drug interactions study could be an opportunistic way to further verify these findings and establish the role of OATP2B1 in the underlying mechanism of rosuvastatin absorption and tissue exposure.

Acknowledgements: This study was sponsored by AbbVie Inc. All authors namely MMP, AP, AS, SK and JE are employee of AbbVie. Inc. and contributed to the part or participated in design, research, and interpretation of the data and/or writing.