TY - JOUR
T1 - Subcutaneous administration, higher age and lower renal function are associated with erythrocyte methotrexate accumulation in Crohn's disease
T2 - a cross-sectional study
AU - van de Meeberg, M. M.
AU - Seinen, M. L.
AU - Fidder, H. H.
AU - Lin, M.
AU - Oldenburg, B.
AU - de Boer, N. K.
AU - Bouma, G.
AU - de Jonge, R.
AU - Dutch Initiative on Crohn and Colitis (ICC)
AU - Bulatović Ćalasan, M.
N1 - Funding Information: This is an investigator-initiated study with financial support of the Dutch Initiative on Crohn’s and Colitis (ICC) and of the Dutch Gastroenterology Foundation (MLDS). The funding bodies MLDS and ICC had no role in the design of the study and collection, analysis, and interpretation of data or in writing the manuscript. Funding Information: The following authors are members of the funding body ICC: GB, NKB, HHF, BO. HHF has served as a speaker for Janssen and Takeda. She has served as a consultant for Takeda, Galapagos and Ferring. She has received a research grant from Takeda. All outside the submitted work. BO has served as a speaker for Takeda, Galapagos, MSD. Grants: Pfizer, Takeda, Ferring. He has served as consultant/advisory board for Janssen, Pfizer, Takeda, Cablon. All outside the submitted work.NKB has served as a speaker for AbbVie and MSD. He has served as consultant and principal investigator for TEVA Pharma BV and Takeda. He has received a (unrestricted) research grant from Dr Falk, TEVA Pharma BV, MLDS and Takeda. All outside the submitted work.GB has served as a speaker for AbbVie and has served as a consultant for Takeda, Roche and Dr Falk, all not related to the submitted work. MMM, MLS, RJ and MBC declare that they have no ethical conflicts to disclose. Publisher Copyright: © 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - BACKGROUND: Methotrexate is an immunomodulatory drug for patients with Crohn's disease. Erythrocyte MTX-polyglutamates (MTX-PG1-5) may be used for therapeutic drug monitoring (TDM) as MTX-PG is thought to mediate MTX's efficacy. Information on determinants of the concentration of MTX-PG in patients with Crohn's disease is lacking. We aim to identify clinical and biochemical determinants of the erythrocyte MTX-PG1-5 and MTX-PGtotal concentration in patients with Crohn's disease. METHODS: Adults with Crohn's disease on methotrexate treatment who visited the outpatient clinic of Amsterdam UMC were included. Erythrocyte MTX-PGs were measured by tandem mass spectrometry. RESULTS: Nineteen patients were included, with a median duration of MTX use of 77 months (range 7-202). Twelve patients received MTX monotherapy, whereas 7 patients were on concomitant TNF-α inhibitors. The mean dose of MTX was 15.5 mg (SD ± 2.8) and 12 (63%) patients used subcutaneous MTX. MTX-PG1-5 were successfully measured in 18 patients, showing substantial variability in concentrations of MTX-PGtotal and individual species. The median MTX-PGtotal was 117.1 nmol/L (range 46.4-258.7) with preferential accumulation of MTX-PG3 (43.1 nmol/L, range 15.3-96.1). Patients on subcutaneous compared to oral MTX had higher median MTX-PG(4,5) levels (55 versus 9 nmol/L, p = 0.01). Higher age (β = 0.71) and lower estimated glomerular filtration rate (β = - 0.52) were associated with a significantly higher MTX-PGtotal concentration (R2 = 0.60, p = 0.001). CONCLUSION: MTX-PG concentrations display a considerable inter-individual variability. Higher MTX-PG accumulation is associated with subcutaneous administration, higher age, and lower renal function in Crohn's disease patients.
AB - BACKGROUND: Methotrexate is an immunomodulatory drug for patients with Crohn's disease. Erythrocyte MTX-polyglutamates (MTX-PG1-5) may be used for therapeutic drug monitoring (TDM) as MTX-PG is thought to mediate MTX's efficacy. Information on determinants of the concentration of MTX-PG in patients with Crohn's disease is lacking. We aim to identify clinical and biochemical determinants of the erythrocyte MTX-PG1-5 and MTX-PGtotal concentration in patients with Crohn's disease. METHODS: Adults with Crohn's disease on methotrexate treatment who visited the outpatient clinic of Amsterdam UMC were included. Erythrocyte MTX-PGs were measured by tandem mass spectrometry. RESULTS: Nineteen patients were included, with a median duration of MTX use of 77 months (range 7-202). Twelve patients received MTX monotherapy, whereas 7 patients were on concomitant TNF-α inhibitors. The mean dose of MTX was 15.5 mg (SD ± 2.8) and 12 (63%) patients used subcutaneous MTX. MTX-PG1-5 were successfully measured in 18 patients, showing substantial variability in concentrations of MTX-PGtotal and individual species. The median MTX-PGtotal was 117.1 nmol/L (range 46.4-258.7) with preferential accumulation of MTX-PG3 (43.1 nmol/L, range 15.3-96.1). Patients on subcutaneous compared to oral MTX had higher median MTX-PG(4,5) levels (55 versus 9 nmol/L, p = 0.01). Higher age (β = 0.71) and lower estimated glomerular filtration rate (β = - 0.52) were associated with a significantly higher MTX-PGtotal concentration (R2 = 0.60, p = 0.001). CONCLUSION: MTX-PG concentrations display a considerable inter-individual variability. Higher MTX-PG accumulation is associated with subcutaneous administration, higher age, and lower renal function in Crohn's disease patients.
KW - Crohn’s disease
KW - Methotrexate
KW - Pharmacokinetics
KW - Therapeutic drug monitoring
UR - http://www.scopus.com/inward/record.url?scp=85135246382&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s12876-022-02439-y
DO - https://doi.org/10.1186/s12876-022-02439-y
M3 - Article
C2 - 35907797
SN - 1471-230X
VL - 22
SP - 365
JO - BMC gastroenterology
JF - BMC gastroenterology
IS - 1
M1 - 365
ER -