Assessment of the relationship between methotrexate polyglutamates in red blood cells and clinical response in patients commencing methotrexate for rheumatoid arthritis
| Autor: | Stephen B. Duffull, Lisa K. Stamp, Julia Korell, Shan Pan, Mei Zhang, Jill Drake, Murray L. Barclay, Judith M. Dalrymple |
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| Rok vydání: | 2014 |
| Předmět: |
musculoskeletal diseases
Adult Male Erythrocytes Arthritis Pharmacology Models Biological Arthritis Rheumatoid Pharmacotherapy immune system diseases medicine Humans heterocyclic compounds Pharmacology (medical) skin and connective tissue diseases Aged medicine.diagnostic_test Polyglutamate business.industry Middle Aged medicine.disease Clinical trial Red blood cell medicine.anatomical_structure Methotrexate Treatment Outcome Polyglutamic Acid Therapeutic drug monitoring Rheumatoid arthritis Antirheumatic Agents Female business medicine.drug |
| Zdroj: | Clinical pharmacokinetics. 53(12) |
| ISSN: | 1179-1926 |
| Popis: | 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.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.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.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. |
| Databáze: | OpenAIRE |
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