Erschienen in:
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
verfasst von:
Shan Pan, Lisa K. Stamp, Stephen B. Duffull, Murray L. Barclay, Judith M. Dalrymple, Jill Drake, Mei Zhang, Julia Korell
Erschienen in:
Clinical Pharmacokinetics
|
Ausgabe 12/2014
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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.