Assessing OATP1B1- and OATP1B3-Mediated Drug-Drug Interaction Potential of Vemurafenib Using R-Value and Physiologically-Based Pharmacokinetic Models

Abstract

Organic anion transporting polypeptides (OATP) 1B1 and OATP1B3 are important determinants of transporter-mediated drug-drug interactions (DDIs). Current studies assessed the OATP1B1 and OATP1B3-mediated DDI potential of vemurafenib, a kinase inhibitor drug with high protein binding and low aqueous solubility, using R-value and physiologically-based pharmacokinetic (PBPK) models. The total half-maximal inhibitory concentration (IC_50,total) values of vemurafenib against OATP1B1 and OATP1B3 were determined in 100% human plasma in transporter-overexpressing human embryonic kidney 293 stable cell lines. The unbound fraction of vemurafenib in human plasma before (f_u,plasma) and after addition into the uptake assay plate (f_u,plasma,inc) were determined by rapid equilibrium dialysis. There was no statistically significant difference between f_u,plasma and f_u,plasma,inc. Vemurafenib IC_50,total values against OATP1B1 and OATP1B3 are 175 ± 82 and 231 ± 26 μM, respectively. The R-values [R = 1 + f_u,plasma × I_in,max/(f_u,plasma,inc × IC_50,total)] were then simplified as R = 1+I_in,max/IC_50,total, and were 1.76 and 1.57 for OATP1B1 and OATP1B3, respectively. The simulated pravastatin AUC ratio was 1.28 when a single dose of pravastatin (40 mg) was co-administered with vemurafenib (960 mg, twice daily) at steady-state, compared to pravastatin alone. Both R-value and PBPK models predict that vemurafenib has the potential to cause OATP1B1- and OATP1B3-mediated DDIs.

Keywords: Drug-drug interactions; Kinase inhibitor drug; OATP1B1; OATP1B3; Total IC(50) approach; Vemurafenib.