Determinants of the elimination of methotrexate and 7-hydroxy-methotrexate following high-dose infusional therapy to cancer patients.

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