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

Joerger, M.
Huitema, A. D. R.
van den Bongard, H. J. G. D.
Baas, P.
Schornagel, J. H.
Schellens, J. H. M.
Beijnen, J. H.

¹Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands
²Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands
³Department of Radiotherapy, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands
⁴Division of Drug Toxicology, Department of Biomedical Analysis, Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

Correspondence: Markus Joerger, MD, Slotervaart Hospital/The Netherlands Cancer Institute, Department of Pharmacy & Pharmacology, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. Tel: + 31 20 512 46 57 Fax: + 31 20 512 47 53 E-mail:[email protected]

M. Joerger is supported by a fellowship grant funded by the European Society of Medical Oncology and by a research grant from the Swiss National Science Foundation (PBBSB-102331).

Received 23 May 2005; Accepted 1 July 2005 PublishedOnlineEarly 27 September 2005

British Journal of Clinical Pharmacology 62(1):p 71-80, July 2006.

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⁻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).

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.