Case study of OATP1B DDI assessment and challenges in drug discovery and development—real-life examples

Predicting the OATP1B DDIs from in vitro data for drugs, especially highly protein bound drugs, remains challenging. Cynomolgus monkey is emerging as a clinically relevant model to provide mechanistic insight regarding the role of OATP1B in drug disposition and interaction. This case study highlights the application of monkey OATP1B model in drug development using the example of the inhibition potential of BMS-919373. BMS-919373 was found to be an inhibitor of OATP1B1/1B3 in vitro. An IVIVE using the static R-value method indicated the possibility of DDI. Dosing monkeys with BMS-919373 at a dose that achieved human equivalent systemic plasma concentration increased rosuvastatin AUC by 11.5-fold in monkeys, whereas the administration that achieved human equivalent portal vein concentrations resulted in a 2.22-fold increase. Clinical DDI studies between BMS-919373 with rosuvastatin indicated that the fold-changes were similar to that in monkeys when BMS-919373 was dosed to achieve human equivalent portal vein concentration. These results confirm the translational value of monkey OATP1B model using the appropriate dosing considerations.