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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

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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 MTXGlu3–5. 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 MTXGlu3–5 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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Acknowledgments

The clinical studies were supported by the Health Research Council of New Zealand and New Zealand Pharmacy Education and Research Foundation. Shan Pan was supported by a University of Otago PhD scholarship.

Ethical standards

The clinical studies were approved by the Upper South B Regional Ethics Committee and were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

All patients gave written informed consent prior to entering the clinical studies.

Conflicts of interest

Shan Pan, Lisa K. Stamp, Stephen B. Duffull, Murray L. Barclay, Judith M. Dalrymple, Jill Drake, Mei Zhang and Julia Korell declare no conflicts of interest.

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Authors and Affiliations

  1. School of Pharmacy, University of Otago, Dunedin, New Zealand

    Shan Pan & Stephen B. Duffull

  2. Department of Medicine, University of Otago, Christchurch, New Zealand

    Lisa K. Stamp, Murray L. Barclay, Jill Drake & Mei Zhang

  3. Department of Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand

    Murray L. Barclay & Judith M. Dalrymple

  4. Toxicology, Canterbury Health Laboratories, Christchurch, New Zealand

    Mei Zhang

  5. Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden

    Julia Korell

  6. Model Answers Pty Ltd, Brisbane, Australia

    Julia Korell

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  1. Shan Pan
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Correspondence to Julia Korell.

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Pan, S., Stamp, L.K., Duffull, S.B. et al. Assessment of the Relationship Between Methotrexate Polyglutamates in Red Blood Cells and Clinical Response in Patients Commencing Methotrexate for Rheumatoid Arthritis. Clin Pharmacokinet 53, 1161–1170 (2014). https://doi.org/10.1007/s40262-014-0179-5

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