Methotrexate Reduces the Clearance of Adalimumab by Increasing the Concentration of Neonatal Fc Receptor in Tissues
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Although pharmacokinetic (PK) interaction effects of methotrexate (MTX) on adalimumab have been found, the mechanism of these effects is still unclear. In this work, effects of MTX on the concentration of neonatal Fc receptor (FcRn) and the role of FcRn in the interaction between MTX and adalimumab were investigated.
The experiment was performed in rats whose FcRn had normal physiological function and also in rats whose FcRn was blocked with FcRn antibody. Rats were randomly assigned to receive placebo or 0.2 mg/kg MTX orally every week while taking one abdominal subcutaneous injection of 0.5 mg/kg adalimumab. The FcRn concentration in tissues and the PK parameters of adalimumab were compared between MTX-treated and placebo groups.
In rats with normally functioning FcRn, the concentrations of FcRn were significantly increased in the liver (F=105.5, p=0.000) and kidney (F=996.312, p=0.000) after treatment with MTX, and the clearance (CL/F) of adalimumab was decreased accordingly (F=4.423, p=0.048). However, in rats injected with FcRn antibody, the concentrations of FcRn in MTX-treated rats were close to that of the placebo rats in the tissues of the liver (F=1.279, p=0.268) and kidney (F=0.661, p=0.424). The CL/F of adalimumab in rats was also not affected by MTX (F=0.002, p=0.961).
FcRn may play a vital role in the interaction between adalimumab and MTX.
KEY WORDSadalimumab drug-drug interaction methotrexate neonatal Fc receptor
AUC from the time of dosing to the last measurable concentration
AUC from the time of dosing extrapolated to infinity based on the last
Apparent total body clearance
Maximum observed concentration
Neonatal Fc receptor
Mean residence time
Time of Cmax
Apparent volume of distribution predicted concentration
Acknowledgements and Disclosures
The work was supported by National Natural Science Foundation of China (grant numbers 81703610 and 81573498); the China Postdoctoral Science Foundation funded project (grant number 2017M612599). The authors declare no conflict of Ainterest.
L.W. and Z.N.C. conceived and designed the study. L.X.L. and Y.W.D. conducted the experiments in rats. W.Q. and L.H. performed the data analysis. L.W. and Z.N.C. authored the manuscript.
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