Determinants of the elimination of methotrexate and 7-hydroxy-methotrexate following high-dose infusional therapy to cancer patients.
Joerger, M. 1,2; Huitema, A. D. R. 1; van den Bongard, H. J. G. D. 3; Baas, P. 2; Schornagel, J. H. 2; Schellens, J. H. M. 2,4; Beijnen, J. H. 1,2,4
[Article]
British Journal of Clinical Pharmacology.
62(1):71-80, July 2006.
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Aims: To characterize determinants of the elimination of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) in patients receiving high-dose MTX therapy (HDMTX).
Methods: 24 and 48-h blood samples from 76 patients receiving HDMTX (dose range 300 mg m-2 to 12 g m-2) were analysed, and concentration-time data were subjected to population pharmacokinetic and covariate analysis using nonlinear mixed-effect modelling (NONMEM).
Results: Treatment-related mortality was 1.3% (one patient with renal failure). Values for MTX clearance (CLMTX) and 7-OH-MTX clearance (CL7-OH-MTX) were estimated at 8.85 and 2 L-1, respectively. Baseline creatinine clearance correlated with CLMTX and CL7-OH-MTX. Concurrent administration of benzimidazoles led to a 27% decrease in CLMTX and a 39% decrease in CL7-OH-MTX. Prior administration of nonsteroidal anti-inflammatory drugs (NSAIDs) resulted in a 16% decrease in CLMTX and a 38% decrease in CL7-OH-MTX. Plasma MTX concentrations were significantly higher in patients also receiving benzimidazoles at 24 h (2.01 [mu]mol L-1vs. 0.66 [mu]mol L-1, P < 10-4) and at 48 h (0.25 [mu]mol L-1vs. 0.12 [mu]mol L-1, P < 10-4). 7-OH-MTX plasma concentrations were also significantly higher in patients with concurrent benzimidazoles as compared with patients without benzimidazoles at 24 h (4.47 [mu]mol L-1vs. 2.52 [mu]mol L-1, P = 0.0009) and at 48 h (1.11 [mu]mol L-1vs. 0.72 [mu]mol L-1, P = 0.031).
Conclusions: In patients receiving HDMTX, concurrent administration of benzimidazoles was associated with a significant decrease of CLMTX and CL7-OH-MTX, resulting in significantly higher plasma concentrations of MTX and 7-OH-MTX. The data suggest that benzimidazole treatment should be seen as a relative contraindication for HDMTX.
Copyright (C) 2006 Blackwell Publishing Ltd.