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Pharmaceutical Research

, 36:157 | Cite as

Methotrexate Reduces the Clearance of Adalimumab by Increasing the Concentration of Neonatal Fc Receptor in Tissues

  • Yuwei Deng
  • Lixiong Liu
  • Wei Qiang
  • Li Hu
  • Lei WangEmail author
  • Zeneng Cheng
Research Paper
  • 78 Downloads

Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusions

FcRn may play a vital role in the interaction between adalimumab and MTX.

KEY WORDS

adalimumab drug-drug interaction methotrexate neonatal Fc receptor 

Abbreviations

(AUClast)

AUC from the time of dosing to the last measurable concentration

(AUCinf)

AUC from the time of dosing extrapolated to infinity based on the last

(CL)

Clearance

(CL/F)

Apparent total body clearance

(Cmax)

Maximum observed concentration

(FcRn)

Neonatal Fc receptor

(MRT)

Mean residence time

(NCA)

Non-compartmental analysis

(PK)

Pharmacokinetic

(Tmax)

Time of Cmax

(V/F)

Apparent volume of distribution predicted concentration

Notes

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.

Author’s contributions

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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yuwei Deng
    • 1
  • Lixiong Liu
    • 2
  • Wei Qiang
    • 1
  • Li Hu
    • 2
  • Lei Wang
    • 1
    • 3
    Email author
  • Zeneng Cheng
    • 1
  1. 1.Research Institute of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical SciencesCentral South UniversityChangshaChina
  2. 2.Department of RheumatologyShenzhen People’s HospitalShenzhenChina
  3. 3.School of Life SciencesCentral South UniversityChangshaChina

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