Arzneimittelforschung 2010; 60(12): 769-775
DOI: 10.1055/s-0031-1296353
Antibiotics · Antimycotics · Antiparasitics · Antiviral Drugs · Chemotherapeutics · Cytostatics
Editio Cantor Verlag Aulendorf (Germany)

High-dose methotrexate in children with acute lymphoblastic leukemia: 7-hydroxymethotrexate systemic exposure and urinary concentrations at the steady state correlate well with those of methotrexate

Jiřina Chládková
1   Department of Paediatrics, Charles University in Prague, Faculty of Medicine and Hospital, Hradec Králové, Czech Republic
Jiří Hak
1   Department of Paediatrics, Charles University in Prague, Faculty of Medicine and Hospital, Hradec Králové, Czech Republic
Jiřina Martínková
2   Department of Pharmacology, Charles University in Prague, Faculty of Medicine, Hradec Králové, Czech Republic
Jaroslav Chládek
2   Department of Pharmacology, Charles University in Prague, Faculty of Medicine, Hradec Králové, Czech Republic
› Author Affiliations
Further Information

Publication History

Publication Date:
03 December 2011 (online)


The present study evaluated the pharmacokinetics of methotrexate (MTX, CAS 59-05-2) and 7-hydroxymethotrexate (7-OHMTX, CAS 5939-37-7) in children with acute lymphoblastic leukemia (ALL) with particular interest devoted to the renal excretion at the steady-state and to the relationships between total (CL) and renal clearances (CLR) of both compounds.

Ten children (seven girls) aged 8.5 years (2.9–16) years with standard or medium-risk ALL received four 24-h i. v. infusions of high-dose MTX (HDMTX, 5 g/m2) with leucovorin (CAS 58-05-9) rescue according to the ALL-BFM-95 protocol. MTX and 7-OHMTX were assayed in plasma and urine by high-performance liquid chromatography.

At the steady-state, the clearance (CL) of MTX (6.28 ± 2.79 l.h−1) was correlated with its CLR (rs = 0.79, p < 0.0001) which accounted for 61% (SD 26%) of the former. There were weak correlations between pretreatment values of creatinine clearance calculated using Schwartz’s formula and the drug’s CL (rs = 0.30, p < 0.05) or CLR (rs = 0.41, p < 0.02). In contrast, the CLR accounted for only 26% (SD 15%) of the metabolite’s CL which was estimated assuming 10% conversion of MTX to 7-OHMTX. The CL values of both compounds were highly correlated (rs = 0.86, p < 0.0001). The CLR of the parent compound was on the average 9-fold higher (range: 3.5− to 17-fold) and was strongly correlated with the CLR of the metabolite (rs = 0.87, p < 0.0001). The ratio 7-OHMTX/MTX of urinary concentrations was between 2.4 and 9.8% with the mean value of 4.1%.

This study suggests that during the 24-h i.v. infusions of HDMTX to children with ALL, the exposure of patients to 7-OHMTX can be reasonably well predicted from the knowledge of MTX concentrations. The steady-state renal CLs, total CLs as well as urinary concentrations of the parent compound and metabolite are highly correlated and the correlation of plasma concentrations is moderate. Therefore, it is unlikely that simultaneous evaluation of 7-OHMTX and MTX steady-state concentrations could improve the predictive performance of the latter towards the response or the risk of complications, although future larger studies should verify this conclusion.

  • References

  • 1 Schrappe M, Reiter A, Zimmermann M, Harbott J, Ludwig WD, Henze G et al Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Munster. Leukemia. 2000; 14: 2205-22
  • 2 Moe PJ, Holen A. High-dose methotrexate in childhood ALL. Pediatr Hematol Oncol. 2000; 17: 615-22
  • 3 Reiter A, Schrappe M, Ludwig WD, Tiemann M, Parwa-resch R, Zimmermann M et al Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood. 2000; 95: 416-21
  • 4 Delepine N, Delepine G, Bacci G, Rosen G, Desbois JC. Influence of methotrexate dose intensity on outcome of patients with high grade osteogenic osteosarcoma. Analysis of the literature. Cancer. 1996; 78: 2127-35
  • 5 Crom WR, Evans WE. Methotrexate. In: Evans WE, Schentag JJ, Jusko WJ. editors. Applied Pharmacokinetics: Principles of therapeutic drug monitoring. Chapter 29 Vancouver (WA): Applied Therapeutics, Inc.; 1992: 1-42
  • 6 Borsi JD, Moe PJ. A comparative study on the pharmacokinetics of methotrexate in a dose range of 0.5 g to 33.6 g/m2 in children with acute lymphoblastic leukemia. Cancer. 1987; 60: 5-13
  • 7 Wolfrom C, Hepp R, Hartmann R, Breithaupt H, Henze G. Pharmacokinetic study of methotrexate, folinic acid and their serum metabolites in children treated with high-dose methotrexate and leucovorin rescue. Eur J Clin Pharmacol. 1990; 39: 377-83
  • 8 Donelli MG, Zucchetti no-given-name, Robatto A, Perlamgeli V, D’lncalci M, Masera G et al Pharmacokinetics of HD-MTX in infants, children, and adolescens with non-B acute lymphoblastic leukemia. Med Pediatr Oncol. 1995; 24: 154-9
  • 9 Odoul F, Le Guellec Ch, Lamagnère JP, Breilh D, Saux M-C, Paintaud G et al Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukaemia using a population pharmacokinetic approach. Fundam Clin Pharmacol. 1999; 13: 595-604
  • 10 Aumente D, Buelga DS, Lukas JC, Gomez P, Torres A, Garcia MJ. Population pharmacokinetics of high-dose methotrexate in children with acute lymphoblastic leukaemia. Clin Pharmacokinet. 2006; 45: 1227-38
  • 11 Plard C, Bressolle F, Fakhoury M, Zhang D, Yacouben K, Rieutord A et al A limited sampling strategy to estimate individual pharmacokinetic parameters of methotrexate in children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 2007; 60: 609-20
  • 12 Winograd B, Lippens RJJ, Oosterbaan MJM, Dirks MJM, Vree TB, van der Klein E. Renal excretion and pharmacokinetics of methotrexate and 7-hydroxy-methotrexate following a 24-h high dose infusion of methotrexate in children. Eur J Pharmacol. 1986; 30: 231-8
  • 13 Evans WE, Crom WR, Abromowitch M, Dodge R, Look AT, Bowman WP et al Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect. N Engl J Med. 1986; 14: 471-7
  • 14 Evans WE, Crom WR, Stewart CF, Bowman WP, Chen CH, Abromowitch M et al Methotrexate systemic clearance influences probability of relapse in children with standard risk acute lymphocytic leukemia. Lancet. 1984; I: 359-62
  • 15 Borsi JD, Moe PJ. Systemic clearance of methotrexate in the prognosis of acute lymphoblastic leukemia in children. Cancer. 1987; 60: 3020-4
  • 16 Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Hui CHH. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med. 1998; 338: 499-505
  • 17 Skärby T, Jönsson P, Hjorth L, Behrentz M, Björk O, Forestier E et al 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; 5: 311-20
  • 18 Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist. 2006; 11: 694-703
  • 19 Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dördelmann M et al German-Austrian-Swiss ALL-BFM Study Group. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008; 111: 4477-89
  • 20 Salamoun J, Frantisek J. Determination of methotrexate and its metabolites 7-hydroxymethotrexate and 2,4 diami-no-N10-methylpteroic acid in biological fluids by liquid chromatography with fluorimetric detection. J Chromatogr. 1986; 378: 173-81
  • 21 Sasaki K, Hosoya R, Wang YM, Raulston GL. Formation and disposition of 7-hydroxymethotrexate in rabbits. Biochem Pharmacol. 1983; 32: 503-7
  • 22 Breithaupt H, Küenzlen E. Pharmacokinetics of methotrexate and 7-hydroxymethotrexate following infusions of high-dose methotrexate. Cancer Treat Rep. 1982; 66: 1733-41
  • 23 Joerger M, Huitema AD, van den Bongard HJ, Baas P, Schornagel JH, Schellens JH et al Determinants of the elimination of methotrexate and 7-hydroxy-methotrexate following high-dose infusional therapy to cancer patients. Br J Clin Pharmacol. 2006; 62: 71-80
  • 24 Schwartz GJ, Haycock GB, Edelmann Jr CM, Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics. 1976; 58: 259-63
  • 25 Lawrenz-Wolf B, Wolfrom C, Frickel C, Fengler R, Wehinger H, Henze G. Severe renal impairment of methotrexate elimination after high dose therapy. Klin Padiatr. 1994; 206: 319-26
  • 26 Sand TE, Jacobsen S. Effect of urine pH and flow on renal clearance of methotrexate. Eur J Clin Pharmacol. 1981; 19: 453-6
  • 27 Albertioni F, Rask C, Schroeder H, Peterson C. Monitoring of methotrexate and 7-hydroxymethotrexate in saliva from children with acute lymphoblastic leukemia receiving high-dose consolidation treatment: relation to oral mucositis. Anticancer Drugs. 1997; 8: 119-24
  • 28 Hempel L, Misselwitz J, Fleck C, Kentouche K, Leder C, Appenroth D et al Influence of high-dose methotrexate therapy (HD-MTX) on glomerular and tubular kidney function. Med Pediatr Oncol. 2003; 40: 348-54
  • 29 Hendel J, Nyfors A. Nonlinear renal elimination kinetics of methotrexate due to saturation of renal tubular reabsorption. Eur J Clin Pharmacol. 1984; 26: 121-4
  • 30 Relling MV, Fairclough D, Ayers D, Crom WR, Rodman JH, Pui CH et al Ewans. Patient characteristics associated with high-risk methotrexate concentrations and toxicity. J Clin Oncol. 1994; 12: 1667-72
  • 31 Joannon P, Oviedo I, Campbell M, Tordecilla J. High-dose methotrexate therapy of childhood acute lymphoblastic leukemia: lack of relation between serum methotrexate concentration and creatinine clearance. Pediatr Blood Cancer. 2004; 43: 17-22
  • 32 Faltaos DW, Hulot JS, Urien S, Morel V, Kaloshi G, Fernandez C et al Population pharmacokinetic study of methotrexate in patients with lymphoid malignancy. Cancer Chemother Pharmacol. 2006; 58: 626-33
  • 33 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: 677-84
  • 34 Borsi J, Sagen E, Romslo I, Moe PJ. Comparative study on the pharmacokinetics of 7-hydroxy-methotrexate after administration of methotrexate in the dose range of 0.5–33.6 g/m2 to children with acute lymphoblastic leukemia. Med Pediatr Oncol. 1990; 18: 217-24