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- Title
Determinants of the elimination of methotrexate and 7-hydroxy-methotrexate following high-dose infusional therapy to cancer patients.
- Authors
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.
- Abstract
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 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 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.
- Subjects
METHOTREXATE; FOLIC acid antagonists; BENZIMIDAZOLES; DRUG interactions; DRUG side effects
- Publication
British Journal of Clinical Pharmacology, 2006, Vol 62, Issue 1, p71
- ISSN
0306-5251
- Publication type
Article
- DOI
10.1111/j.1365-2125.2005.02513.x