Risk factors for delayed methotrexate elimination in pediatric patients with hematological malignancies: a retrospective analysis

doi:10.5246/jcps.2022.10.064

Abstract

Abstract:

Delayed elimination of methotrexate (MTX) is a major clinical concern in patients receiving high-dose MTX (HD-MTX) therapy. In the present study, we aimed to retrospectively explore the factors associated with MTX concentrations and elimination delay in pediatric patients with hematological malignancies. Cycles of HD-MTX therapy were categorized into the normal elimination group and delayed elimination group according to the serum MTX concentrations at 24 (C₂₄) or 42 h (C₄₂) after the start of MTX therapy. Clinical characteristics associated with MTX concentrations and elimination delay were assessed by χ² test, Fisher’s exact test, Mann-Whitney test, or Spearman's correlation coefficient. Generalized Estimating Equations (GEE) were used to adjust for the clustering effects of multiple cycles in one patient and confounders. A total of 43 patients with 138 cycles of HD-MTX chemotherapy were included and evaluated in the current study. Dose, white blood cells (WBC), hemoglobin (HB), and blood urea nitrogen (BUN) were significantly correlated with MTX C₂₄ (all P < 0.05). No significant correlations were noticed between baseline characteristics and MTX C₄₂. Delayed MTX elimination was observed in 34 (24.6%) courses. Dose, WBC, HB, BUN, and concurrent infection were the significant risk factors for delayed MTX elimination (all P < 0.05). Our study identified several risk factors associated with MTX levels and elimination, which might be used to recognize patients with a high risk of delayed MTX elimination. However, the findings need to be confirmed in further large-scale studies.

Key words: Methotrexate, Elimination delay, Therapeutic drug monitoring

Supporting:

Miao Li, Xiaoyan Kong, Shumei Wang. Risk factors for delayed methotrexate elimination in pediatric patients with hematological malignancies: a retrospective analysis[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(10): 746-754.

Figures/Tables 5

Table 1. Baseline characteristics for 138 courses of HD-MTX in 43 patients.

Table 2. Correlations between baseline characteristics and serum MTX concentrations (unadjusted for clustering).

Table 3. Correlations between baseline characteristics and serum MTX concentrations by GEE analysis.

Table 4. Relations between baseline characteristics and delayed MTX elimination by GEE analysis.

References 24

[1]	Larry H, M.; Taub, J.W.; Ravindranath, Y.; Proefke, S.A.; Wong, S.C.; Gimotty, P.; Buck, S.; Wright, J.E.; Rosowsky, A. Elevated dihydrofolate reductase and impaired methotrexate transport as elements in methotrexate resistance in childhood acute lymphoblastic leukemia. Blood. 1995, 85, 500–509.
[2]	Liu, J.Y.; Tian, C. Synthesis and evaluation of 8-deaza-5,6,7,8-tetrahydromethotrexate derivatives as dihydrofolate reductase inhibitors. J. Chin. Pharm. Sci. 2012, 21, 142–148.
[3]	Scott, D.L.; Wolfe, F.; Huizinga, T.W. Rheumatoid arthritis. Lancet. 2010, 376, 1094–1108.
[4]	Rajitha, P.; Biswas, R.; Sabitha, M.; Jayakumar, R. Methotrexate in the treatment of psoriasis and rheumatoid arthritis: mechanistic insights, current issues and novel delivery approaches. Curr. Pharm. Des. 2017, 23, 3550–3566.
[5]	Jolivet, J.; Cowan, K.H.; Curt, G.A.; Clendeninn, N.J.; Chabner, B.A. The pharmacology and clinical use of methotrexate. N Engl. J. Med. 1983, 309, 1094–1104.
[6]	Levêque, D.; Santucci, R.; Gourieux, B.; Herbrecht, R. Pharmacokinetic drug-drug interactions with methotrexate in oncology. Expert Rev. Clin. Pharmacol. 2011, 4, 743–750.
[7]	Schmiegelow, K.; Nielsen, S.N.; Frandsen, T.L.; Nersting, J. Mercaptopurine/Methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction. J. Pediatr. Hematol. Oncol. 2014, 36, 503–517.
[8]	Stoller, R.G.; Hande, K.R.; Jacobs, S.A.; Rosenberg, S.A.; Chabner, B.A. Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. N Engl. J. Med. 1977, 297, 630–634.
[9]	Martelli, N.; Mathieu, O.; Margueritte, G.; Bozonnat, M.C.; Daurès, J.P.; Bressolle, F.; Hillaire-Buys, D.; Peyrière, H. Methotrexate pharmacokinetics in childhood acute lymphoblastic leukaemia: a prognostic value? J. Clin. Pharm. Ther. 2011, 36, 237–245.
[10]	Schmidt, D.; Kristensen, K.; Schroeder, H.; Wehner, P.S.; Rosthøj, S.; Heldrup, J.; Damsgaard, L.; Schmiegelow, K.; Mikkelsen, T.S. Plasma creatinine as predictor of delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia: a Danish population-based study. Pediatr. Blood Cancer. 2019, 66, e27637.
[11]	Evans, W.E.; Crom, W.R.; Abromowitch, M.; Dodge, R.; Look, A.T.; Bowman, W.P.; George, S.L.; Pui, C.H. Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect. N Engl. J. Med. 1986, 314, 471–477.
[12]	Evans, W.E.; Relling, M.V.; Rodman, J.H.; Crom, W.R.; Boyett, J.M.; Pui, C.H. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl. J. Med. 1998, 338, 499–505.
[13]	Drost, S.A.; Wentzell, J.R.; Giguère, P.; McLurg, D.L.; Sabloff, M.; Kanji, S.; Nguyen, T.T. Outcomes associated with reducing the urine alkalinization threshold in patients receiving high-dose methotrexate. Pharmacother. J. Hum. Pharmacol. Drug Ther. 2017, 37, 684–691.
[14]	Ranchon, F.; Vantard, N.; Henin, E.; Bachy, E.; Sarkozy, C.; Karlin, L.; Bouafia-Sauvy, F.; Gouraud, A.; Schwiertz, V.; Bourbon, E.; Baudouin, A.; Caffin, A.G.; Vial, T.; Salles, G.; Rioufol, C. Delayed methotrexate elimination: Incidence, interaction with antacid drugs, and clinical consequences? Hematol. Oncol. 2018, 36, 399–406.
[15]	Rask, C.; Albertioni, F.; Bentzen, S.M.; Schroeder, H.; Peterson, C. Clinical and pharmacokinetic risk factors for high-dose methotrexate-induced toxicity in children with acute lymphoblastic leukemia: a logistic regression analysis. Acta Oncol. Stock. Swed. 1998, 37, 277–284.
[16]	Boerrigter, E.; Crul, M. A non-interventional retrospective cohort study of the interaction between methotrexate and proton pump inhibitors or aspirin. Ann. Pharm. Françaises. 2017, 75, 344–348.
[17]	Inose, R.; Takahashi, K.; Nanno, S.; Hino, M.; Nagayama, K. Calcium channel blockers possibly delay the elimination of plasma methotrexate in patients receiving high-dose methotrexate therapy. J. Chemother. 2019, 31, 30–34.
[18]	Skärby, T.; Jönsson, P.; Hjorth, L.; Behrentz, M.; Björk, O.; Forestier, E.; Jarfelt, M.; Lönnerholm, G.; Höglund, P. High-dose methotrexate: on the relationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acute lymphoblastic leukaemia (ALL). Cancer Chemother. Pharmacol. 2003, 51, 311–320.
[19]	Fukuhara, K.; Ikawa, K.; Morikawa, N.; Kumagai, K. Population pharmacokinetics of high-dose methotrexate in Japanese adult patients with malignancies: a concurrent analysis of the serum and urine concentration data. J. Clin. Pharm. Ther. 2008, 33, 677–684.
[20]	Xu, W.Q.; Zhang, L.Y.; Chen, X.Y.; Pan, B.H.; Mao, J.Q.; Song, H.; Li, J.Y.; Tang, Y.M. Serum creatinine and creatinine clearance for predicting plasma methotrexate concentrations after high-dose methotrexate chemotherapy for the treatment for childhood lymphoblastic malignancies. Cancer Chemother. Pharmacol .2014, 73, 79–86.
[21]	Schmiegelow, K. Advances in individual prediction of methotrexate toxicity: a review. Br. J. Haematol. 2009, 146, 489–503.
[22]	Suzuki, K.; Doki, K.; Homma, M.; Tamaki, H.; Hori, S.; Ohtani, H.; Sawada, Y.; Kohda, Y. Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy. Br. J. Clin. Pharmacol. 2009, 67, 44–49.
[23]	Kagawa, Y.; Mukohara, R.; Hori, H.; Kawasaki, H.; Komada, Y.; Kojima, M. Fever as a risk factor causing delayed elimination of methotrexate in pediatric patients receiving high doses of cancer chemotherapy. Cancer Chemother. Pharmacol. 2004, 54, 34–38.
[24]	Huang, C.; Xia, F.; Xue, L.; Liu, L.; Bian, Y.; Jin, Z.; Miao, L. Coadministration of vindesine with high-dose methotrexate therapy increases acute kidney injury via BCRP, MRP2, and OAT1/OAT3. Cancer Chemother. Pharmacol. 2020, 85, 433–441.