Pharmacogenetic hSLCO1B1*14-Guided Dosing of Methotrexate in Transgenic Arthritic Mice Normalizes Exposure and Response.

Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disease that negatively affects ~100,000 children under the age of 16 in the United States. About ~30% of these patients fail first-line drug therapy with low-dose methotrexate (MTX) due to poor tolerability or lack of efficacy. The SLCO1B1*14 allele is associated with increased MTX clearance and has been linked to reduced overall drug exposure and nonresponse to MTX in JIA patients. Herein, we describe transgenic hSLCO1B1*14 and hSLCO1B1*1 DBA1/J mSlco1b2 knock-out mice, which we used to assess arthritic response to MTX using the collagen-induced arthritis model. Mass spectrometry-based proteomics analysis revealed that OATP1B1 protein abundance was 2.1-fold higher in hSLCO1B1*14 mice compared to hSLCO1B1*1 mice. Following treatment with 1 mg/kg MTX for 3 weeks, hSLCO1B1*14 mice exhibited a 39% increase in median arthritic disease burden (p = 0.02) and a 22% reduction in MTX AUC (p = 0.14) compared to hSLCO1B1*1 mice. Pharmacokinetic modeling estimated that the hSLCO1B1*14 mice would need a 30% higher dose to equalize exposure and response to hSLCO1B1*1 mice. When hSLCO1B1*14 mice received 1.3 mg/kg MTX, the arthritic disease burden and overall MTX exposure were less than the 1 mg/kg MTX in hSLCO1B1*1 mice, reinforcing that differences in MTX elimination and therapeutic response can be accounted for by using pharmacogenetic-guided dosing of MTX in JIA patients.