Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Methotrexate (MTX) is known to improve exposure and clinical outcome to anti-tumor necrosis factor (TNF) therapy. While the precise mechanism of action for the pharmacokinetic interaction is still elusive, immunosuppression and reduction in the likelihood of antidrug antibodies are likely significant contributors. This pilot study evaluated the impact of MTX polyglutamation on anti-TNF exposure.
The study was cross sectional by design, multicentered (three sites), and enrolled 230 consecutive adult rheumatoid arthritis subjects under MTX in combination with infliximab (61 subjects), adalimumab (83 subjects) or etanercept (86 subjects) for at least 12 weeks. At the time of a single visit, anti-coagulated blood was collected immediately before the infliximab infusion (trough) or randomly in relation to the last subcutaneous injection of adalimumab or etanercept. Steady state trough infliximabemia, random adalimumabemia or etanerceptemia were determined using a TNF reporter gene assay with chemiluminescent detection (expressed as µg/ml plasma). Red blood cells (RBC) MTX polyglutamates (MTXPG3) were determined using liquid chromatography (expressed as nmol/L RBC). C-reactive protein (CRP) levels were determined using standard chemistry techniques (expressed as mg/L). Statistical analysis consisted of multivariate linear regression with anti-TNF exposure as dependent variable and RBC MTXPG3 as independent predictor, adjusting estimates for TNF dosage, obesity status (BMI>30 Kg/m2) and CRP levels. Estimates are reported as average±SEM.
All subjects enrolled in this study (59±1 years; 82% females) were under MTX therapy 8.8±0.4 years and prescribed anti-TNF therapy for 5.2±0.2 years. MTX dosage was 16±0.4 mg/week and RBC MTXPG3 levels were 36±1 nmol/L. CRP levels were 8.7±0.6 mg/L with 35% obese subjects. Exposure to Infliximab (7.4±0.6 mg/Kg every 8 weeks), adalimumab (42±1 mg every other week) and etanercept (49±0.7 mg weekly) was 11.8±0.8 µg/ml, 6.2±0.9 µg/ml, and 3.2±0.2 µg/ml respectively. Higher anti-TNF dosage resulted in higher exposure to all biologics, while obesity status had a negative impact on infliximab and adalimumab exposure. Elevated CRP levels tended to be associated with lower exposure to all monoclonal antibodies. Heightened MTXPG3 levels resulted in increased infliximabemia (partial R2=0.09; p<0.01) and adalimumabemia (partial R2=0.06; p=0.02) while polyglutamation had no impact on etanercept exposure.
These data are consistent with the notion that MTX polyglutamation may impact exposure to infliximab and adalimumab that are immunogenic and prone to anti-idiotype antibody formation. Because etanercept is a fusion TNF receptor construct with little incidence of antidrug antibodies, the impact of MTX metabolism on its exposure is negligible.
To cite this abstract in AMA style:Dervieux T, Kremer JM, O'Malley T, Kivitz AJ, Conklin J, Weinblatt M. Differing Contribution of Methotrexate Polyglutamation to Infliximab and Adalimumab Exposure As Compared to Etanercept [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/differing-contribution-of-methotrexate-polyglutamation-to-infliximab-and-adalimumab-exposure-as-compared-to-etanercept/. Accessed January 15, 2021.
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