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

British Journal of Clinical Pharmacology - Tập 62 Số 1 - Trang 71-80 - 2006
Markus Joerger1,2, Alwin D. R. Huitema2, H.J.G.D. van den Bongard3, Paul Baas1, Jan H. Schornagel1, Jan H.M. Schellens1,4, Jos H. Beijnen1,2,4
1Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/the Netherlands Cancer Institute, Amsterdam, The Netherlands
2Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands
3Department of Radiotherapy, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands and
4Division of Drug Toxicology, Department of Biomedical Analysis, Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

Tóm tắt

AimsTo characterize determinants of the elimination of methotrexate (MTX) and 7‐hydroxy‐methotrexate (7‐OH‐MTX) in patients receiving high‐dose MTX therapy (HDMTX).Methods24 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).ResultsTreatment‐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−1vs. 0.66 µmol L−1, P < 10−4) and at 48 h (0.25 µmol L−1vs. 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−1vs. 2.52 µmol L−1, P = 0.0009) and at 48 h (1.11 µmol L−1vs. 0.72 µmol L−1, P = 0.031).ConclusionsIn 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.

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British Journal of Clinical Pharmacology

Tập 62 Số 1

71-80

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