Simplification of a pharmacokinetic model for red blood cell methotrexate disposition

Pan, Shuting; Korell, Julia; Stamp, Lisa K.; Duffull, Stephen B.

doi:10.1007/s00228-015-1951-7

Cited by 4 publications

(9 citation statements)

References 20 publications

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“…Therefore, we explored the relationship between dose and MTX‐PG 3‐5 concentrations based on the prior lumped PK‐model structure of Pan et al 16,17 . In short, a population plasma‐PK model and first‐order kinetics to MTX‐PGs was used to describe the formation of MTX polyglutamates using two lumped compartments 16,17,21 .…”

Section: Methodsmentioning

confidence: 99%

“…Based on studies of Pan et al, we focused on the association between MTX-PG 3-5 and change in DAS28, using a nonlinear association. 16,17,21 Pan et al used 5 transit compartments to describe the delay between MTX-PG 3-5 and ΔDAS28. As our data did not show a clear delay in achieving steady-state of MTX-PG 3-5 vs. PD, we then tested a direct response model: with E t is the predicted DAS28 at time t, E 0 is the DAS28 score at baseline, E max the maximum effect on DAS28, EC 50 the MTX-PG 3-5 concentration at 50% of the maximum effect, and C PG3-5 the MTX-PG 3-5 concentration.…”

Section: Pd Modelmentioning

confidence: 99%

“…In a subsequent study in these patients, RBC-MTX-PG 3-5 showed the highest activity; concentrations of these species were associated with a reduction in disease activity. 17 To combine this knowledge while making it more suitable for clinical practice, we conducted a comprehensive PK/PD analysis. Using modeling and simulations, we were able to examine and predict all timedependent dose-exposure-response associations, examine potential delays in response, and assess the effects of dose adjustments.…”

mentioning

confidence: 99%

“…first associated the MTX‐PG formation of each individual MTX‐PG and correlated the long chain MTX‐PG 3‐5 with clinical response in 14 patients. In a subsequent study in these patients, RBC‐MTX‐PG 3‐5 showed the highest activity; concentrations of these species were associated with a reduction in disease activity 17 . To combine this knowledge while making it more suitable for clinical practice, we conducted a comprehensive PK/PD analysis.…”

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confidence: 99%

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Methotrexate Polyglutamates Exposure – Response Modeling in a Large Cohort of Rheumatoid Arthritis Patients Starting Methotrexate

Hebing

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Gosselt

et al. 2023

Clin Pharma and Therapeutics

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Methotrexate polyglutamates (MTX‐PG) concentrations in red blood cells (RBCs) have been suggested as a biomarker of response in patients with rheumatoid arthritis (RA) receiving low‐dose MTX therapy. We investigated the association and interpatient variability between RBC‐MTX‐PG3‐5‐exposure and response in patients with RA starting MTX. Data of three prospective cohorts were available. The relationship between exposure and Disease Activity Score in 28 joints (DAS28) was analyzed using a population pharmacokinetic‐pharmacodynamic model. Relevant covariates were tested using full covariate modeling and backward elimination. From 395 patients, 3,401 MTX‐PG concentrations and 1,337 DAS28 measurements were available between 0 and 300 days after MTX treatment onset. The developed model adequately described the time course of MTX‐PG3‐5 and DAS28. The median MTX‐PG3‐5 level at month 1 was 30.9 nmol/L (interquartile range (IQR): 23.6–43.7; n = 41) and at month 3: 69.3 nmol/L (IQR: 17.9–41.2; n = 351). Clearance of MTX‐PG3‐5 from RBCs was 28% lower (95% confidence interval (CI): 23.6–32.8%) in a woman and 10% lower (95% CI: 7.7–12.4%) in a 65‐year‐old compared with a 35‐year‐old patient. MTX‐PG3‐5 concentrations associated with DAS28: half‐maximal effective concentration (EC50) was 9.14 nmol/L (95% CI: 4.2 nmol/L‐14.1 nmol/L). EF at 80% (EC80) above 47 nmol/L was regarded as the optimal response. Independent of the MTX‐PG 3–5 – response association, co‐administration of disease‐modifying antirheumatic drugs and corticosteroids improved response (additive effect on maximum effect (Emax)), whereas smoking, high body mass index and low albumin decreased Emax. In patients with RA starting MTX, RBC‐MTX‐PG3‐5 was associated with clinical response. A dose increase is suggested when MTX‐PG3‐5 at month 1 is below 9.15 nmol/L, continued with the same dose when the concentration is above 47 nmol/L, and consider other treatment options above 78 nmol/L from 3 months onwards.

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Section: Methodsmentioning

confidence: 99%

Section: Pd Modelmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Methotrexate Polyglutamates Exposure – Response Modeling in a Large Cohort of Rheumatoid Arthritis Patients Starting Methotrexate

Hebing

Bartelink

Gosselt

et al. 2023

Clin Pharma and Therapeutics

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“…10 Compared to MTX, the glutamylated MTX (MTXPG 2-7 ) have increased polarity and a higher anionic feature, and poor affinity for multidrug resistance-associated proteins, resulting in prolonged intracellular retention. 11,12 Evidence suggests that MTXPGs display not only longer half-lives but also higher efficacy than MTX. 13,14 Additionally, long-chain MTXPGs (MTXPG 3-7 ) have higher inhibition effects on key enzymes (dihydrofolic acid reductase, thymidylate synthase, and 5-aminoimidazole 4-carboxamide ribonucleotide transformylase) over short-chain MTXPGs (MTX, MTXPG 2 ).…”

Section: Introductionmentioning

confidence: 99%

Methotrexate Polyglutamates Analysis by Chromatography Methods in Biological Matrices: A Review

et al. 2021

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Methotrexate (MTX) is used as an immunosuppressant and antineoplastic drug in clinical practice. MTX is a parent drug and converts to MTX polyglutamates (MTXPGs) to exhibit its biological activity. Clinical studies found that MTXPGs levels were associated with MTX response and toxicities, especially at low dose. Due to huge variance of MTX response and toxicities between individuals, therapeutic drug monitoring is necessary for its individualized therapy. Various chromatography methods coupled with ultraviolet-visible detector, fluorescence detector and mass spectrometry have been reported for MTXPGs analysis in various biological matrices. The aim of this paper is to review the chromatographic based methods for the measurement of total and/or individual MTXPGs. We have searched Embase, Science Direct and PubMed databases using 'methotrexate polyglutamate' and 'chromatography', 745 articles were found and 14 articles were included. The key steps for method development (sample pretreatment, parameter optimization of liquid chromatography and mass spectrometry, selection of internal standard) and validation (lower limit of quantitation, accuracy, precision, recovery, matrix effect and stability) were analyzed and summarized, which might be helpful for researchers to develop their own methods.

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Effect of total glucosides of paeony and Tripterygium wilfordii polyglycosides on erythrocyte methotrexate polyglutamates in rats, analysed using ultra-high-performance liquid chromatography-tandem mass spectrometry

et al. 2021

Journal of Pharmacy and Pharmacology

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Objectives The aim of the study was to explore the effect of total glucosides of paeony (TGP) and Tripterygium wilfordii polyglycosides (TWP) on erythrocyte methotrexate polyglutamates (MTXPGs), the metabolites of methotrexate (MTX). Methods An ultra-high-performance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS) method was developed to determine MTXPGs. The effects of MTXPGs were analysed using 24 male Sprague-Dawley rats that were randomly divided into the MTX alone, MTX-TGP combined, and MTX-TWP combined groups. Rats were administered MTX at a dose of 0.9 mg/kg once a week, TGP at 0.054 g/kg and TWP at 1.8 mg/kg three times a day. Venous blood (1.0 ml) was collected at weeks 2, 4, 6, 9, 12 and 15 and then analysed using the developed UPLC-MS/MS method. Key findings Specificity, linear range, inter-and intra-day precision, recovery, matrix effect and stability of MTXPGs met the standard regulations. This method was successfully used for the detection of MTXPGs. After administration of MTX alone, erythrocyte MTXPGs increased and accumulated in a time- and dose-dependent manner. Compared to MTX alone, the combination with TGP significantly decreased the content of total MTXPGs and short-chain MTXPGs (Methotrexate [MTX/MTXPG1] and 4-amino-10-methylpteroyldiglutamic acid [MTXPG2], P < 0.05), but had no significant effect on long-chain MTXPGs (4-amino-10-methylpteroyltriglutamic acid [MTXPG3], P > 0.05) and very long-chain MTXPGs (4-amino-10-methylpteroyltetraglutamic acid [MTXPG4] and 4-amino-10-methylpteroylpentaglutamic acid [MTXPG5], P > 0.05) at week 15. The combination of MTX with TWP had no significant effect on the content of total MTXPGs, short-chain MTXPGs and long-chain MTXPGs (P > 0.05), but it significantly decreased the content of very long-chain MTXPGs (P < 0.05) at week 15. Conclusions The UPLC-MS/MS method was successfully used to determine MTXPGs in rat erythrocytes. TGP and TWP in combination with MTX affected the production of MTXPGs of different chain lengths in erythrocytes.

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Simplification of a pharmacokinetic model for red blood cell methotrexate disposition

Abstract: This study illustrates the application of model simplification processes to an existing model for MTX RBC PK. The same techniques illustrated in our study may be adopted by other studies with similar interest.

Cited by 4 publications

References 20 publications

Methotrexate Polyglutamates Exposure – Response Modeling in a Large Cohort of Rheumatoid Arthritis Patients Starting Methotrexate

Methotrexate Polyglutamates Exposure – Response Modeling in a Large Cohort of Rheumatoid Arthritis Patients Starting Methotrexate

Methotrexate Polyglutamates Analysis by Chromatography Methods in Biological Matrices: A Review

Effect of total glucosides of paeony and Tripterygium wilfordii polyglycosides on erythrocyte methotrexate polyglutamates in rats, analysed using ultra-high-performance liquid chromatography-tandem mass spectrometry

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