Toward pharmacogenetic SLCO1B1‐guided dosing of methotrexate in arthritis using a murine Slco1b2 knockout model

Abstract

Low-dose methotrexate (MTX) is a first-line therapy for the treatment of arthritis. However, there is considerable inter-individual variability in MTX exposure following standard dosing. Polymorphisms in SLCO1B1 significantly effect MTX clearance, altering therapeutic response. One decreased function variant, rs4149056 (c.521T>C, Val174Ala), slows MTX clearance and in vitro uptake of MTX. This phenotype was recapitulated in a mouse model using a knockout (KO) of the murine orthologue, Slco1b2. Our objective was to investigate the impact of this phenotype on the pharmacokinetics and therapeutic outcomes of low-dose MTX in a murine model of collagen-induced arthritis (CIA). We evaluated response to MTX in mice with CIA using wildtype (WT), heterozygous, and KO Slco1b2 mice on a DBA1/J background. Arthritis was macroscopically evaluated daily to quantify disease progression. Mice received 2 mg/kg or a pharmacogenetically-guided MTX dose subcutaneously 3 times a week for 2 weeks. MTX concentrations were collected at the end of the study and exposure (day*µM) was estimated using a two-compartment model. Mice displayed a 7-fold range in MTX exposure and revealed a significant exposure-response relationship (p=0.0027). KO mice receiving the 2 mg/kg dosing regimen had 2.3-fold greater exposure to MTX (p<0.0001) and a 66% reduction in overall disease progression (p=0.011) compared to WT mice. However, exposure and response were equivalent when pharmacogenetically-guided dosing was used. These studies demonstrate that an exposure-response relationship exists for MTX and that Slco1b2 genotype affects MTX exposure and therapeutic response. Such evidence supports the use of SLCO1B1-pharmacogenetic dosing of low-dose methotrexate for patients with arthritis.

Can Pharmacogenetic Variants in TPMT, MTHFR and SLCO1B1 Genes Be Used as Potential Markers of Outcome Prediction in Systemic Sclerosis Patients?

“…As demonstrated pharmacogenetic markers of response to initial therapy with MTX and maintenance therapy with AZA in other diseases with proven roles in action and clearance of these medicaments [21,24,25,[37][38][39], variants in TPMT, MTHFR and SLCO1B1 genes (rs1800460, rs1142345, rs1801133 and rs4149056 respectively) were selected for investigation in patients with SSc.…”

“…Median age was 59.5 with interquartile range 53.25-63. Most patients (39) developed PF, while FVC/DLCO > 1,6 was the least represented of five followed outcomes. No statistical significance was found in occurrence of severe diseases outcomes between patients that received different medications.…”

Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model

“…However, it is also used in low doses to effectively treat inflammatory diseases such as rheumatoid arthritis and Crohn’s disease ( 62 , 63 ). The methotrexate doses in animal experiments ranges from 2mg/kg to 200mg/kg ( 64 , 65 ). For the dose in our experiments, due to lack of hamster pharmacokinetics we used the mice pharmacokinetics by Lobo ED’s lab ( 66 ), and to avoid methotrexate-induced toxicity ( 67 ) to consider a lower test dose of 2mg/kg/day for short-term treatment.…”