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 mu mol L(-1)vs. 0.66 mu mol L-1, P < 10(-4)) and at 48 h (0.25 mu mol L(-1)vs. 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(-1)vs. 2.52 mu mol L-1, P = 0.0009) and at 48 h (1.11 mu mol L(-1)vs. 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.