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 (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.