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Determinants of the elimination of methotrexate and 7‐hydroxy‐methotrexate following high‐dose infusional therapy to cancer patients
Author(s) -
Joerger M.,
Huitema A. D. R.,
Van Den Bongard H. J. G. D.,
Baas P.,
Schornagel J. H.,
Schellens J. H. M.,
Beijnen J. H.
Publication year - 2006
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2005.02513.x
Subject(s) - methotrexate , medicine , nonmem , antifolate , pharmacokinetics , pharmacology , antimetabolite , population , creatinine , gastroenterology , environmental health
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 (CL MTX ) and 7‐OH‐MTX clearance (CL 7‐OH‐MTX ) were estimated at 8.85 and 2 L −1 , respectively. Baseline creatinine clearance correlated with CL MTX and CL 7‐OH‐MTX . Concurrent administration of benzimidazoles led to a 27% decrease in CL MTX and a 39% decrease in CL 7‐OH‐MTX . Prior administration of nonsteroidal anti‐inflammatory drugs (NSAIDs) resulted in a 16% decrease in CL MTX and a 38% decrease in CL 7‐OH‐MTX . Plasma MTX concentrations were significantly higher in patients also receiving benzimidazoles at 24 h (2.01 µmol L −1 vs. 0.66 µmol L −1 , P < 10 −4 ) and at 48 h (0.25 µmol L −1 vs. 0.12 µmol 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 µmol L −1 vs. 2.52 µmol L −1 , P = 0.0009) and at 48 h (1.11 µmol L −1 vs. 0.72 µmol L −1 , P = 0.031). Conclusions In patients receiving HDMTX, concurrent administration of benzimidazoles was associated with a significant decrease of CL MTX and CL 7‐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.