TY - JOUR
T1 - Therapeutic drug monitoring of methotrexate in patients with Crohn's disease
AU - van de Meeberg, Maartje M.
AU - Fidder, Herma H.
AU - Oldenburg, Bas
AU - Sundaresan, Janani
AU - Struys, Eduard A.
AU - Montazeri, Nahid S. M.
AU - Mares, Wout G. N.
AU - Mahmmod, Nofel
AU - van Asseldonk, Dirk P.
AU - Lutgens, Maurice W. M. D.
AU - Kuyvenhoven, Johan P.
AU - Rietdijk, Svend T.
AU - Nissen, Loes H. C.
AU - Koehestanie, Parweez
AU - de Boer, Nanne K. H.
AU - de Jonge, Robert
AU - Bouma, Gerd
AU - Bulatović Ćalasan, Maja
N1 - Funding Information: This study was funded by the Dutch gastroenterology foundation (“Maag Lever Darm Stichting”). The funding body had no role in data collection, analysis, and interpretation or in writing the manuscript. Publisher Copyright: © 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.
PY - 2023/12
Y1 - 2023/12
N2 - Background: 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). Aim: 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. Results: 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-PG3 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. Conclusions: Higher MTX-PG3 concentrations are related to better methotrexate drug survival and decreased FCP levels. Therefore, MTX-PG3 could be used for TDM if a target concentration can be established.
AB - Background: 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). Aim: 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. Results: 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-PG3 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. Conclusions: Higher MTX-PG3 concentrations are related to better methotrexate drug survival and decreased FCP levels. Therefore, MTX-PG3 could be used for TDM if a target concentration can be established.
UR - http://www.scopus.com/inward/record.url?scp=85173082955&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/apt.17719
DO - https://doi.org/10.1111/apt.17719
M3 - Article
C2 - 37767910
SN - 0269-2813
VL - 58
SP - 1151
EP - 1162
JO - Alimentary Pharmacology and Therapeutics
JF - Alimentary Pharmacology and Therapeutics
IS - 11-12
ER -