PI-048 - GREATER METHOTREXATE EXPOSURE IN HSLCO1B1*14 TRANSGENIC MICE AS THE RESULT OF PHARMACOGENOMIC GUIDED-DOSING NORMALIZES THERAPEUTIC RESPONSE

F. Gooden¹, Z. Taylor², B. Meier³, L. Ramsey⁴; ¹University of Cincinnati/Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, ²Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, ³University of Cincinnati, Cincinnati, OH, USA, ⁴Children's Mercy, Kansas City, MO, United States.

Background: Low-dose methotrexate (MTX) is a front-line disease modifying anti-rheumatic drug used to treat autoimmune diseases such as juvenile idiopathic arthritis (JIA). Single nucleotide polymorphisms (SNPs) in the gene SLCO1B1 encoding for liver transporter organic anion transporting protein 1B1 resulting in increased functionality are expressed in 8-20% of the population and have been associated with reduced efficacy in retrospective meta-analyses of JIA patients. The purpose of this study was to evaluate whether application of a pharmacogenomic (PGx) dose of MTX to arthritic transgenic hSLCO1b1*14 mice results in better therapeutic outcomes.

Methods: hSLCO1b1*1 and *14 mice underwent a pharmacokinetic (PK) dosing study of 1 mg/kg. Concentrations were measured by LC/MS/MS and exposure estimated using a two-compartment model and Bayesian estimation in MW/Pharm. Comparison of the modeled curves calculated a 30% dose increase to 1.3 mg/kg PGx-guided dose and this was validated in PK dosing. Uniform and PGx-guided doses were applied to mice undergoing the collagen-induced arthritis protocol and then treated from Days 14-35 with subcutaneous MTX injection.

Results: Administration of uniform 1 mg/kg MTX dose resulted in inadequate control of arthritis in *14 mice compared to *1. Therapeutic response and MTX AUC were normalized between *1 and *14 mice by the application of a PGx-guided dose of 1.3 mg/kg.

Conclusion: These studies demonstrate that arthritis in *14 mice is inadequately controlled by uniform dosing of MTX but is effectively lowered by PGx-guided dosing, which reinforces MTX effects by increasing exposure to MTX in *14 mice. JIA patients with a *14 allele may benefit from PGx-guided dosing of MTX.