Therapeutic drug monitoring of methotrexate in patients with Crohn's disease

• Published in: Alimentary pharmacology & therapeutics Vol. 58; no. 11-12; pp. 1151 - 1162
• Main Authors: van de Meeberg, Maartje M, Fidder, Herma H, Oldenburg, Bas, Sundaresan, Janani, Struys, Eduard A, Montazeri, Nahid S M, Mares, Wout G N, Mahmmod, Nofel, van Asseldonk, Dirk P, Lutgens, Maurice W M D, Kuyvenhoven, Johan P, Rietdijk, Svend T, Nissen, Loes H C, Koehestanie, Parweez, de Boer, Nanne K H, de Jonge, Robert, Bouma, Gerd, Bulatović Ćalasan, Maja
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-12-2023
• Subjects: Adult; Aged; Antirheumatic Agents - therapeutic use; Chemical and Drug Induced Liver Injury; Crohn Disease - chemically induced; Crohn Disease - drug therapy; Crohn's disease; Crohns disease; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Erythrocytes; Female; Hepatotoxicity; Humans; Intolerance; Male; Methotrexate; Methotrexate - adverse effects; Middle Aged; Prospective Studies; Survival; Therapeutic drug monitoring; Toxicity; Treatment Outcome
• ISSN: 0269-2813; 1365-2036; 1365-2036
• DOI: 10.1111/apt.17719

Therapeutic drug monitoring (TDM) has the potential to improve efficacy and diminish side effects. Measuring methotrexate-polyglutamate (MTX-PG) in erythrocytes might enable TDM for methotrexate in patients with Crohn's disease (CD).
To investigate the relationship between MTX-PGs and methotrexate drug survival, efficacy and toxicity METHODS: In a multicentre prospective cohort study, patients with CD starting subcutaneous methotrexate without biologics were included and followed for 12 months. Primary outcome was subcutaneous methotrexate discontinuation or requirement for step-up therapy. Secondary outcomes included faecal calprotectin (FCP), Harvey Bradshaw Index (HBI), hepatotoxicity and gastrointestinal intolerance. Erythrocyte MTX-PGs were analysed at weeks 8, 12, 24 and 52 or upon treatment discontinuation.
We included 80 patients with CD (mean age 55 ± 13y, 35% male) with a median FCP of 268 μg/g (IQR 73-480). After the 12-month visit, 21 patients (26%) were still on subcutaneous methotrexate monotherapy. Twenty-one patients stopped because of disease activity, 29 because of toxicity, and four for both reasons. Five patients ended study participation or stopped methotrexate for another reason. A higher MTX-PG
concentration was associated with a higher rate of methotrexate drug survival (HR 0.86, 95% CI 0.75-0.99), lower FCP (β -3.7, SE 1.3, p < 0.01) and with biochemical response (FCP ≤250 if baseline >250 μg/g; OR 1.1, 95% CI 1.0-1.3). Higher MTX-PGs were associated with less gastrointestinal intolerance. There was no robust association between MTX-PGs and HBI or hepatotoxicity.
Higher MTX-PG
concentrations are related to better methotrexate drug survival and decreased FCP levels. Therefore, MTX-PG
could be used for TDM if a target concentration can be established.