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. 2022 Jul 30;22(1):365.
doi: 10.1186/s12876-022-02439-y.

Subcutaneous administration, higher age and lower renal function are associated with erythrocyte methotrexate accumulation in Crohn's disease: a cross-sectional study

M M van de Meeberg  1   2 , M L Seinen  3 , H H Fidder  4 , M Lin  5 , B Oldenburg  4 , N K de Boer  6 , G Bouma  6 , R de Jonge  5 , M Bulatović Ćalasan  5   7 ; Dutch Initiative on Crohn and Colitis (ICC)
Affiliations

Subcutaneous administration, higher age and lower renal function are associated with erythrocyte methotrexate accumulation in Crohn's disease: a cross-sectional study

M M van de Meeberg et al. BMC Gastroenterol. .

Abstract

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.

Keywords: Crohn’s disease; Methotrexate; Pharmacokinetics; Therapeutic drug monitoring.

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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1
Boxplot of erythrocyte MTX-PGn concentrations in nmol/L for CD patients using oral (orange) versus subcutaneous (green) MTX. Median MTX-PG concentrations (range) for all patients were as follows: MTX-PG1 26.7 (9.9–170.1), MTX-PG2 17.4 (7.5–24.8), MTX-PG3 43.1 (15.3–96.1), MTX-PG4 19.7 (2.4–60.1), MTX-PG5 9.4 (1.1–24.1), MTX-PGtotal 117.1 (46.4–258.7) nmol/L
Fig. 2
Fig. 2
Linear regression of [A] MTX-PG(4,5) concentration versus age [B] MTX-PG(4,5) concentration versus eGFR [C] MTX-PG5 concentration versus erythrocyte folate concentration. β[A] = 0.78 (p = 0.0002), β[B] = − 0.58 (p = 0.01), β[C] = 0.68 (p = 0.01). Results of individuals patients are displayed as a scatter plot, with orange dots for oral MTX users and green dots for subcutaneous MTX users
Fig. 3
Fig. 3
Mean erythrocyte MTX-PGtotal concentration with standard deviation of our study population and other published IBD populations. MTX-PG concentrations expressed in nmol/8 × 1012 red blood cells as nmol/L, because the articles used packed or washed erythrocytes with a Red Blood Cell International System of Units Reference Range of 8 × 1012 red blood cells per litre.17–19
See this image and copyright information in PMC

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