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- Korell, Julia, et al.
(author)
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Comparison of intracellular methotrexate kinetics in red blood cells with the kinetics in other cell types
- 2014
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In: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 77:3, s. 493-497
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Journal article (peer-reviewed)abstract
- AimTo assess the similarities in intracellular pharmacokinetics (PK) of methotrexate (MTX) in red blood cells (RBCs) and other cell lines. MethodsThree previously published PK models for intracellular MTX and MTX polyglutamate (MTXGlu(2-5)) concentrations were used: (i) a model for the kinetics in RBCs, (ii) a model for the kinetics in human breast cancer cells (HBCCs) and (iii) a model for the kinetics in various white blood cell (WBC) lines. All three models were used to simulate the response in a typical individual receiving 10mg oral MTX once weekly and the predicted steady-state concentrations (C-ss) and time to C-ss (t(ss)) were compared. ResultsThe HBCC model showed a lower C-ss for MTXGlu(2 and 3) and higher C-ss for MTXGlu(4 and 5) compared with the RBC PK model, while t(ss) and overall intracellular MTX exposure appeared similar. The WBC PK model showed much lower C-ss for the parent MTXGlu(1) and of t(ss) for all MTXGlu(n), as well as a much lower cumulative C-ss for MTXGlu(2-7) for the majority of the WBC cell lines. ConclusionRBC kinetics of MTX differ from the kinetics in other cell types such as WBCs and HBCCs to a variable degree. It is possible that similarly diverse profiles may exist across other cell lines, including those on the causal path in rheumatoid arthritis. Hence, there may not necessarily be a clear link between RBC MTX concentrations and disease control in rheumatoid arthritis.
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| 2. |
- Pan, Shan, et al.
(author)
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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
- 2014
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In: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 53:12, s. 1161-1170
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Journal article (peer-reviewed)abstract
- Therapeutic drug monitoring in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX, MTXGlu(1)) 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.
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