Development and validation of a methotrexate adherence assay

Bluett, James; Riba-Garcia, Isabel; Verstappen, Suzanne; Wendling, Thierry; Ogungbenro, Kayode; Unwin, Richard D.; Barton, Anne

doi:10.1136/annrheumdis-2019-215446

Cited by 20 publications

(27 citation statements)

References 29 publications

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“…Methotrexate biomarker: This biochemical assay uses liquid chromatography–tandem mass spectrometry performed on a Waters TQ-S Micro Triple Quadrupole Mass Spectrometry 21. It provides an objective measurement of adherence and has been developed with drug concentration limits according to methotrexate dose and detects methotrexate partial omission or delayed ingestion.…”

Section: Discussionmentioning

confidence: 99%

“…An additional mechanistic aim was to explore the efficiency of the serological response in terms of neutralisation. A sensitivity analysis of participants’ adherence to methotrexate based on a validated bioassay will be undertaken 21…”

Section: Introductionmentioning

confidence: 99%

“…To explore the validity of anti-spike RBD antibody and neutralisation titres to SARS-CoV-2 booster vaccine in participants adherent to methotrexate at each time point based on a validated biochemical assay21 (mechanistic substudy).…”

Section: Introductionmentioning

confidence: 99%

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Effects of temporarily suspending low-dose methotrexate treatment for 2 weeks after SARS-CoV-2 vaccine booster on vaccine response in immunosuppressed adults with inflammatory conditions: protocol for a multicentre randomised controlled trial and nested mechanistic substudy (Vaccine Response On/Off Methotrexate (VROOM) study)

et al. 2022

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IntroductionIt is unknown if a temporary break in long-term immune-suppressive treatment after vaccination against COVID-19 improves vaccine response. The objective of this study was to evaluate if a 2-week interruption in low-dose weekly methotrexate treatment after SARS-CoV-2 vaccine boosters enhances the immune response compared with continuing treatment in adults with autoimmune inflammatory conditions.Methods and analysisAn open-label, pragmatic, prospective, parallel group, randomised controlled superiority trial with internal feasibility assessment and nested mechanistic substudy will be conducted in rheumatology and dermatology clinics in approximately 25 UK hospitals. The sample size is 560, randomised 1:1 to intervention and usual care arms. The main outcome measure is anti-spike receptor-binding domain (RBD) antibody level, collected at prebooster (baseline), 4 weeks (primary outcome) and 12 weeks (secondary outcome) post booster vaccination. Other secondary outcome measures are patient global assessments of disease activity, disease flares and their treatment, EuroQol 5- dimention 5-level (EQ-5D-5L), self-reported adherence with advice to interrupt or continue methotrexate, neutralising antibody titre against SARS-CoV-2 (mechanistic substudy) and oral methotrexate biochemical adherence (mechanistic substudy). Analysis of B-cell memory and T-cell responses at baseline and weeks 4 and 12 will be investigated subject to obtaining additional funding. The principal analysis will be performed on the groups as randomised (ie, intention to treat). The difference between the study arms in anti-spike RBD antibody level will be estimated using mixed effects model, allowing for repeated measures clustered within participants. The models will be adjusted for randomisation factors and prior SARS-CoV-2 infection status.Ethics and disseminationThis study was approved by the Leeds West Research Ethics Committee and Health Research Authority (REC reference: 21/HRA/3483, IRAS 303827). Participants will be required to give written informed consent before taking part in the trial. Dissemination will be via peer review publications, newsletters and conferences. Results will be communicated to policymakers.Trial registration numberISRCTN11442263.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of temporarily suspending low-dose methotrexate treatment for 2 weeks after SARS-CoV-2 vaccine booster on vaccine response in immunosuppressed adults with inflammatory conditions: protocol for a multicentre randomised controlled trial and nested mechanistic substudy (Vaccine Response On/Off Methotrexate (VROOM) study)

et al. 2022

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“…The widespread problem of medication nonadherence has fuelled interest in the application of hyphenated MS-based (predominantly LC-MS/MS [qqq]) bioanalytical assays to adherence assessment studies in other clinical areas including cancer in situations where oral chemotherapy drugs are prescribed [101][102][103][104][105][106][107][108], immunosuppressant therapy [109][110][111][112], schizophrenia [113,114], depression [115,116], epilepsy [117], asthma [118][119][120][121], infectious diseases [122,123], tuberculosis [124,125], arthritis [126,127], inflammatory bowel disease [128] and attention deficit hyperactivity disorder (ADHD) [129][130][131].…”

Section: Clinical Applications Of Hyphenated Ms Techniques For Assessmentioning

confidence: 99%

Hyphenated mass spectrometry techniques for assessing medication adherence: advantages, challenges, clinical applications and future perspectives

Tanna

Ogwu

Lawson

2020

Clinical Chemistry and Laboratory Medicine (CCLM)

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Nonadherence to prescribed pharmacotherapy is an understated public health problem globally and is costing many patients their chance to return to good health and healthcare systems billions. Clinicians need an accurate assessment of adherence to medications to aid the clinical decision-making process in the event of poor patient progress and to maximise the patient health outcomes from the drug therapies prescribed. An overview of indirect and direct methods used to measure medication adherence is presented, highlighting the potential for accurate measuring of drugs in biological samples using hyphenated mass spectrometry (MS) techniques to provide healthcare professionals with a reliable evidence base for clinical decision making. In this review we summarise published applications of hyphenated MS techniques for a diverse range of clinical areas demonstrating the rise in the use of such direct methods for assessing medication adherence. Although liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods using plasma, serum and urine samples are the most popular, in recent years increased attention has been given to liquid chromatography high-resolution mass spectrometry (LC-HRMS) methods and alternative biosample matrices including hair, saliva and blood microsamples. The advantages and challenges of using hyphenated MS techniques to address this healthcare problem are also discussed alongside future perspectives.

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“…Methotrexate (MTX) is an antimetabolite for folic acid ( Bluett et al, 2019 ). MTX is an essential component of therapy for acute lymphoblastic leukemia (ALL) and is active against many types of cancer; however, MTX use needs to be monitored for potential side effects, such as bone marrow suppression, alopecia, stomatitis and the development of hepatic fibrosis or cirrhosis ( De Abreu et al, 2015 ; Karami, et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Relationship Between the Free and Total Methotrexate Plasma Concentration in Children and Application to Predict the Toxicity of HD-MTX

Dong

Guo

et al. 2021

Front. Pharmacol.

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High-dose methotrexate (HD-MTX) can be highly effective as well as extremely toxic. Many drug molecules can bind to plasma proteins to different extents in vivo, whereas only the free drug can reach the site of action to exert a pharmacological effect and cause toxicity. However, free MTX concentrations in plasma have not been reported. Traditional analyses of free drugs are both cumbersome and inaccurate. We collected 92 plasma samples from 52 children diagnosed with ALL or NHL or other lymphomas that were treated with HD-MTX. The hollow fiber centrifugal ultrafiltration (HFCF-UF) was used to prepare plasma samples for analysis of the free MTX concentration. Protein precipitation was employed to measure the total MTX concentration. The HFCF-UF is a simple method involving a step of ordinary centrifugation; the validation parameters for the methodological results were satisfactory and fell within the acceptance criteria. A linearity coefficient r2 of 0.910 was obtained for the correlation between the free and total MTX plasma concentrations in 92 plasma samples. However, the free and total MTX concentrations was only weakly correlated in 16 clinical plasma specimens with total MTX concentrations >2 μmol L−1 (r2 = 0.760). Both the free and total MTX concentrations at 42 h were negatively correlated with the creatinine clearance (CCr) level (P = 0.023, r = −0.236 for total MTX and P = 0.020, r = −0.241for free MTX, respectively). The free MTX concentration could not be accurately estimated from the total MTX concentration for patients with high MTX levels which are conditions under which toxic reactions are more likely to occur. High plasma MTX levels could become a predictor of the occurrence of MTX nephrotoxicity to draw people's attention. The proposed HFCF-UF method is a simple and accurate way to evaluate efficacy and toxicity in clinical therapeutic drug monitoring.

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Development and validation of a methotrexate adherence assay

Cited by 20 publications

References 29 publications

Hyphenated mass spectrometry techniques for assessing medication adherence: advantages, challenges, clinical applications and future perspectives

Relationship Between the Free and Total Methotrexate Plasma Concentration in Children and Application to Predict the Toxicity of HD-MTX

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