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01-12-2014 | Original Research Article

Assessment of the Relationship Between Methotrexate Polyglutamates in Red Blood Cells and Clinical Response in Patients Commencing Methotrexate for Rheumatoid Arthritis

Authors: Shan Pan, Lisa K. Stamp, Stephen B. Duffull, Murray L. Barclay, Judith M. Dalrymple, Jill Drake, Mei Zhang, Julia Korell

Published in: Clinical Pharmacokinetics | Issue 12/2014

Abstract

Background and Objectives

Therapeutic drug monitoring in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX, MTXGlu₁) has not been established. In this study, we aim to explore the relationship between red blood cell (RBC) concentrations of MTX and its polyglutamate metabolites (MTXGlu_n; n = 2, 3, 4, 5) and clinical response in RA patients commencing MTX.

Methods

The binding activity of MTXGlu_n to three putative enzymes involved in the MTX mechanism of action—dihydrofolate reductase, thymidylate synthase, and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase—was simulated. RBC MTXGlu_n concentrations that gave the highest inhibition activity across all three enzymes were linked with the disease activity score DAS28-3v (C-reactive protein [CRP]). A population pharmacokinetic–pharmacodynamic model was developed to describe the relationship between RBC MTX polyglutamate concentrations and clinical response in 12 RA patients commencing MTX.

Results

The highest inhibition activity was with RBC MTXGlu_3–5. These polyglutamates were further evaluated for their relationship with DAS28-3v (CRP). Three of the 12 patients had a high DAS28-3v (CRP) at baseline (mean = 6.1) and showed a delayed response to MTX treatment. The remaining nine patients with a lower DAS28-3v (CRP) baseline (mean = 3.6) showed an immediate response. The developed MTX pharmacokinetic–pharmacodynamic model provided an acceptable description of the observed DAS28-3v (CRP) across all patients.

Conclusions

The developed model describes a longitudinal relationship between RBC MTXGlu_3–5 concentrations and DAS28-3v (CRP) in patients with RA commencing MTX. Further work is required to determine whether measurement of RBC MTX polyglutamates might be useful for dose individualisation in patients with RA.

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Title: Assessment of the Relationship Between Methotrexate Polyglutamates in Red Blood Cells and Clinical Response in Patients Commencing Methotrexate for Rheumatoid Arthritis
Authors: Shan Pan
Lisa K. Stamp
Stephen B. Duffull
Murray L. Barclay
Judith M. Dalrymple
Jill Drake
Mei Zhang
Julia Korell
Publication date: 01-12-2014
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 12/2014
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-014-0179-5

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Assessment of the Relationship Between Methotrexate Polyglutamates in Red Blood Cells and Clinical Response in Patients Commencing Methotrexate for Rheumatoid Arthritis

Abstract

Background and Objectives

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background and Objectives

Methods

Results

Conclusions

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Acknowledgement to Referees