M. Joerger(1,2) A.D.R. Huitema(1) H.J.G.D. van den Bongard(3) O. van Tellingen(4) P. Baas(2) J.H. Schornagel(2) J.H.M.Schellens(2,5) J.H. Beijnen(1,2,5)
(1) Department of Pharmacy & Pharmacology, Slotervaart Hospital / The Netherlands Cancer, Amsterdam, The Netherlands(2) Department of Medical Oncology, Antoni van Leeuwenhoek Hospital / The Netherlands Cancer (3) Department of Radiotherapy, Antoni van Leeuwenhoek Hospital / The Netherlands Cancer(4) Department of Clinical Chemistry, Antoni van Leeuwenhoek Hospital / The Netherlands Cancer Institute, (5) Division of Drug Toxicology, Department of Biomedical Analysis, Faculty of PharmaceuticalSciences, Utrecht University, Utrecht, The Netherlands
Objectives: The identification of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) pharmacokinetics and its determinants is very useful in providing guidelines to prevent potentially fatal nephrotoxicity from high-dose MTX (HDMTX) schedules. MTX is prone to drug interactions, particularly synergistic nephrotoxicity with non-steroidal anti-inflammatory drugs (NSAIDs), benzimidazoles, penicillin and sulphonamides among others.
Methods: Routine 24- and 48-hr blood samples were collected in 76 patients after having received a total of 308 courses of HDMTX (dose range 300mg/m2 to 12g/m2). Intensive sampling was available from 21 patients. Leucovorin rescue was started 24 hrs after the start of MTX and continued dependent on MTX plasma levels. MTX and 7-OH-MTX concentration-time data were subjected to a population pharmacokinetic and covariate analysis using nonlinear mixed-effect modeling (NONMEM).
Results: Treatment-related mortality was 1.3% (1 patient with fatal renal failure). A three-compartment model best fitted the concentration-time data of MTX, while a two-compartment model best fitted the concentration-time data of 7-OH-MTX. Assuming 10% formation of 7-OH-MTX from MTX, MTX clearance (CLMTX) was estimated at 8.85 L/hr, 7-OH-MTX clearance (CL7-OH-MTX) at 2.00 L/hr. Creatinine clearance (CLCREA) and comedication with benzimidazoles and NSAIDs were significant determinants of both CLMTX and CL7-OH-MTX. Comedication with NSAIDs led to a 16% reduction of CLMTX and a 38% reduction of CL7-OH-MTX, while comedication with benzimidazoles led to a 27% reduction of CLMTX and a 39% reduction of CL7-OH-MTX. A decrease of CLCREA from a median of 87 ml/min to 60 ml/min (lower limit of normal) resulted in a 13% decrease of CLMTX and a 20% decrease of CL7-OH-MTX. Median MTX plasma concentrations at 24 and 48 hours were significantly higher in patients receiving benzimidazoles or NSAIDs as compared to patients without the respective comedication.
Conclusions: Coadministration of benzimidazoles or NSAIDs resulted in decreased CLMTX and CL7-OH-MTX and an increased risk for HDMTX-associated (nephro)toxicity. Patient self-medication of over-the-counter drugs should especially be assessed in this context, before HDMTX is started. The presented data suggest that the use of benzimidazoles and/or NSAIDs should be seen as a relative contraindication for HDMTX.
Reference: PAGE 14 (2005) Abstr 696 [www.page-meeting.org/?abstract=696]
Poster: poster