Plasma and urine levels of methotrexate and 7‐hydroxymethotrexate in children with all during maintenance therapy with weekly oral methotrexate

Skoglund, Kathleen A.; Söderhäll, Stefan; Beck, Olof; Peterson, Curt; Wennberg, Mona; Hayder, Salah; Björk, Olle

doi:10.1002/mpo.2950220307

Cited by 12 publications

(10 citation statements)

References 18 publications

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“…This in contrast with other published assays. 11,12 No discrepancies were seen in 7-OH-MTX formation in our study population.…”

Section: Discussionmentioning

confidence: 61%

“…The assay had a lower limit of quanti cation (LOQ) of 0.02 nM (CV 8.3%) for MTX and 0.16 nM for the metabolite 7-OH-MTX, which are the lowest LOQs for MTX published so far. 11,12 Recovery over a concentration range of 0.16 to 1.6 nM was 91.5 to 93.9% and 105.2 to 114.8% for MTX and 7-OH-MTX, respectively. This ultrasensitive method enabled us to detect the metabolite 7-OH-MTX during the entire dosing interval and to adjust the adherence limits for detection of true-positive adherence in >95% of patients.…”

Section: Methotrexate Assay Speci Cationsmentioning

confidence: 95%

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Adherence to low-dose methotrexate in children with juvenile idiopathic arthritis using a sensitive methotrexate assay

Möhlmann,

de Roock,

Egas

et al. 2024

Preprint

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Background: Low-dose weekly methotrexate is the mainstay of treatment in juvenile idiopathic arthritis. Unfortunately, a substantial part of patients has insufficient efficacy of methotrexate. A potential cause of this inadequate response is suboptimal drug adherence. The aim of this study was to assess methotrexate adherence in juvenile idiopathic arthritis patients by quantification of methotrexate concentrations in plasma. Secondly, the association between methotrexate concentrations and either self-reported adherence issues, or concomitant use of biologics was examined. Methods: This was a retrospective, observational study using plasma samples from juvenile idiopathic arthritis patients. An ultrasensitive liquid chromatography-tandem mass spectrometry method was developed for quantification of methotrexate and its metabolite 7-hydroxy-methotrexate in plasma. The determined methotrexate plasma concentrations in juvenile idiopathic arthritis patients were compared with corresponding adherence limits, categorising them as either adherent or possibly non-adherent to methotrexate therapy. Results: Plasma samples of 43 patients with juvenile idiopathic arthritis were analysed. Adherence to methotrexate in this population was 88% shortly after initiation of methotrexate therapy and decreased to 77% after one year of treatment. Teenagers were more at risk for non-adherence (p=0.002). We could not find an association between methotrexate adherence with either self-reported adherence issues, nor with the use of concomitant biological treatment (p=1.00 and p=0.27, respectively; Fisher’s Exact). Conclusions: Quantification of methotrexate in plasma is a feasible and objective method to assess adherence in patients using low-dose weekly methotrexate. In clinical practice, the use of this method could be a helpful tool for physicians to refute or support suspicion of non-adherence to methotrexate therapy.

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“…This in contrast with other published assays. 11,12 No discrepancies were seen in 7-OH-MTX formation in our study population.…”

Section: Discussionmentioning

confidence: 61%

Section: Methotrexate Assay Speci Cationsmentioning

confidence: 95%

Adherence to low-dose methotrexate in children with juvenile idiopathic arthritis using a sensitive methotrexate assay

Möhlmann,

de Roock,

Egas

et al. 2024

Preprint

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“…In this article a simple and fast method for the determination of methotrexate in serum is described that has equal precision and accuracy to other similar methods (Salamoun et al, 1986;Skoglund et al, 1994). A full chromatography takes 10 minutes.…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of Rapid and Sensitive HPLC Method for the Determination of Methotrexate in Human Serum

et al. 2010

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Methotrexate competitively inhibits dihydrofolic acid reductase and thereby inhibits DNA synthesis and cellular replication.This study describes a simple and fast high-performance liquid chromatography method for the determination of methotrexate [MTX] in serum.samples were collected from adult cancer patients receiving high dose MTX at Mahathma Gandhi Memorial hospital (Warangal,AP.India) at various time intervals after the end of each infusion. Serum was deproteinized with trichloroacetic acid and the supernatant was injected into a 250×4.6 mm octadecylsilane column. Mobile phase was made of TRIS-phosphate buffer (pH 5.7): methanol: acetonitrile (70:20:10) with a flow rate of 1ml/min. Ultraviolet detection was done at 313 nm and at ambient temperature. Para aminoacetophenone was used as internal standard. Methotrexate and internal standard retention times were 4.6 and 9.5 minutes, respectively. Results showed that reproducibility (precision) of method within a day was 2.6 to 6 percent and between days was 5.5 to 9.5 percent. The recovery of the method was between 61.5 and 72.7 percent. The quantitation limit of the method for methotrexate was 0.1μM. This method is suitable for quantitation of methotrexate after infusion of high doses of this drug and has good accuracy, precision and quantitation limit.

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“…Our novel assay has previously been used to study the pharmacokinetics of oral MTX in maintenance therapy of childhood ALL [26], but that limited study did not permit evaluation of age dependency. Wallace et al used a dihydrofolate reductase inhibition assay to study the plasma pharmacokinetics of MTX in children with JRA given 0.11-0.60 mg. kg -1 • week -1 [27].…”

Section: Discussionmentioning

confidence: 99%

Methotrexate in juvenile rheumatoid arthritis

Albertioni

Flatø

Seideman

et al. 1995

Eur J Clin Pharmacol

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Children with juvenile rheumatoid arthritis (JRA) have been reported to require higher doses (per kg body weight) of methotrexate (MTX) than adults with rheumatoid arthritis to control their disease. The purpose of the present study was to characterise the plasma pharmacokinetics of MTX and its major metabolite, 7-hydroxymethotrexate (7-OHMTX) in children, and to compare the results with those previously obtained in adults. Thirteen patients (age 5-16 y) with JRA (median disease duration 5.5 y) were studied after once weekly oral administration of MTX (median 0.21 mg.kg-1). The analytical method was sufficiently sensitive to permit determination of plasma and urinary concentrations of MTX and 7-OHMTX during the entire dose interval in most of the patients. The dose normalized area under the plasma concentration versus time-curve (AUC) of MTX increased with the age of the children and was lower than previously found in adults. The dose normalized AUC of 7-OHMTX was not dependent on age. No correlation was found between the AUCs of MTX and 7-OHMTX. The results suggest that the age-dependence of the pharmacokinetics of MTX might explain the observation that at least some children require higher doses of MTX than adults to obtain a sufficient therapeutic effect.

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Plasma and urine levels of methotrexate and 7‐hydroxymethotrexate in children with all during maintenance therapy with weekly oral methotrexate

Cited by 12 publications

References 18 publications

Adherence to low-dose methotrexate in children with juvenile idiopathic arthritis using a sensitive methotrexate assay

Adherence to low-dose methotrexate in children with juvenile idiopathic arthritis using a sensitive methotrexate assay

Development and Validation of Rapid and Sensitive HPLC Method for the Determination of Methotrexate in Human Serum

Methotrexate in juvenile rheumatoid arthritis

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