TY - JOUR
T1 - Drivers of Methotrexate Polyglutamate Concentration in Erythrocytes
T2 - Insights from Immune-Mediated Inflammatory Diseases and Pediatric Acute Lymphoblastic Leukemia
AU - Sundaresan, Janani
AU - Hamelink, Wout J.
AU - Hebing, Renske C.F.
AU - van de Meeberg, Maartje
AU - Janssen Bonás, Montse
AU - van der Sluis, Inge M.
AU - de Jong, Pascal H.P.
AU - Heymans, Martijn
AU - de Jonge, Robert
AU - de Rotte, Maurits C.F.J.
AU - Bulatović-Ćalasan, Maja
N1 - Publisher Copyright:
© 2026 by the authors.
PY - 2026/2/4
Y1 - 2026/2/4
N2 - Background/Objectives: Methotrexate (MTX) is a cornerstone drug used to treat immune-mediated inflammatory diseases (IMIDs) in low doses (10–30 mg/week), and malignancies in high doses (5000 mg/m2/2 weeks). Its active metabolites, Methotrexate polyglutamates (MTX-PG2–5), quantified in erythrocytes, are associated with efficacy. This study aimed to compare erythrocyte MTX-PG concentrations in patients with IMIDs and pediatric acute lymphoblastic leukemia (ped-ALL) treated with low-dose or high-dose MTX, respectively, and to identify clinical, demographic, and treatment-related factors influencing their concentration. Methods: A total of 567 patients with rheumatoid arthritis, juvenile idiopathic arthritis, Crohn’s disease, sarcoidosis, and ped-ALL were included. Erythrocyte MTX-PG concentration data was collected after 3 months (2.5 months for ped-ALL patients) of MTX-use. Multivariate linear regressing modelling adjusting for age, sex, body mass index (BMI), smoking status, starting MTX dose, route of MTX administration, use of predniso(lo)ne, disease-modifying anti-rheumatic drugs (DMARDs), and folic (or folinic) acid was performed. Results: Intravenous high-dose MTX increased MTX-PG4&5 accumulation. Despite 50-fold higher doses in ped-ALL, MTX-PG2–5sum concentrations were similar to those seen with subcutaneous low-dose MTX used in IMIDs. Age positively influenced MTX-PG concentrations, while DMARD use reduced MTX-PG2–3&5 concentrations. Interestingly, predniso(lo)ne use was associated with higher MTX-PG4&5 concentrations and folic (or folinic) acid with higher MTX-PG3–5 concentrations. Conclusions: This is the first study to compare erythrocyte MTX-PG concentration in low-dose and high-dose patients. Intravenous high-dose MTX administration increased long-chain MTX-PG4&5 concentrations, with MTX-PG2–5sum concentrations similar compared to low-dose subcutaneous MTX use. This study demonstrated that route of administration, age, and concomitant therapies such as DMARDs, predniso(lo)ne, and folic (or folinic) acid significantly influence MTX-PG concentrations.
AB - Background/Objectives: Methotrexate (MTX) is a cornerstone drug used to treat immune-mediated inflammatory diseases (IMIDs) in low doses (10–30 mg/week), and malignancies in high doses (5000 mg/m2/2 weeks). Its active metabolites, Methotrexate polyglutamates (MTX-PG2–5), quantified in erythrocytes, are associated with efficacy. This study aimed to compare erythrocyte MTX-PG concentrations in patients with IMIDs and pediatric acute lymphoblastic leukemia (ped-ALL) treated with low-dose or high-dose MTX, respectively, and to identify clinical, demographic, and treatment-related factors influencing their concentration. Methods: A total of 567 patients with rheumatoid arthritis, juvenile idiopathic arthritis, Crohn’s disease, sarcoidosis, and ped-ALL were included. Erythrocyte MTX-PG concentration data was collected after 3 months (2.5 months for ped-ALL patients) of MTX-use. Multivariate linear regressing modelling adjusting for age, sex, body mass index (BMI), smoking status, starting MTX dose, route of MTX administration, use of predniso(lo)ne, disease-modifying anti-rheumatic drugs (DMARDs), and folic (or folinic) acid was performed. Results: Intravenous high-dose MTX increased MTX-PG4&5 accumulation. Despite 50-fold higher doses in ped-ALL, MTX-PG2–5sum concentrations were similar to those seen with subcutaneous low-dose MTX used in IMIDs. Age positively influenced MTX-PG concentrations, while DMARD use reduced MTX-PG2–3&5 concentrations. Interestingly, predniso(lo)ne use was associated with higher MTX-PG4&5 concentrations and folic (or folinic) acid with higher MTX-PG3–5 concentrations. Conclusions: This is the first study to compare erythrocyte MTX-PG concentration in low-dose and high-dose patients. Intravenous high-dose MTX administration increased long-chain MTX-PG4&5 concentrations, with MTX-PG2–5sum concentrations similar compared to low-dose subcutaneous MTX use. This study demonstrated that route of administration, age, and concomitant therapies such as DMARDs, predniso(lo)ne, and folic (or folinic) acid significantly influence MTX-PG concentrations.
KW - immune-mediated inflammatory diseases
KW - methotrexate polyglutamate
KW - multivariate linear regression modelling
KW - pediatric acute lymphoblastic leukemia
KW - pharmacokinetics and drug metabolism
UR - https://www.scopus.com/pages/publications/105031261964
UR - https://www.mendeley.com/catalogue/27a5c19d-bc9c-309c-816f-b7a0f43f3100/
U2 - 10.3390/ph19020267
DO - 10.3390/ph19020267
M3 - Article
C2 - 41754808
AN - SCOPUS:105031261964
SN - 1424-8247
VL - 19
JO - Pharmaceuticals
JF - Pharmaceuticals
IS - 2
M1 - 267
ER -