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 micromol L-1vs. 0.66 micromol L-1, P<10(-4)) and at 48 h (0.25 micromol L-1vs. 0.12 micromol 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 micromol L-1vs. 2.52 micromol L-1, P=0.0009) and at 48 h (1.11 micromol L-1vs. 0.72 micromol 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.
journal_name
Br J Clin Pharmacoljournal_title
British journal of clinical pharmacologyauthors
Joerger M,Huitema AD,van den Bongard HJ,Baas P,Schornagel JH,Schellens JH,Beijnen JHdoi
10.1111/j.1365-2125.2005.02513.xsubject
Has Abstractpub_date
2006-07-01 00:00:00pages
71-80issue
1eissn
0306-5251issn
1365-2125pii
BCP2513journal_volume
62pub_type
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