Abstract
Pleural effusions, ascites, and renal dysfunction decrease the plasma excretion of methotrexate (MTX). However, it is not known what effect these complications have on MTX clearance when they arise after the plasma MTX concentration has fallen to an undetectable level. We describe the clinical course and pharmacokinetics of MTX in a patient with acute lymphoblastic leukemia who experienced pleural effusions, ascites, and renal failure during the weeks after treatment with high-dose MTX (1.63 g/m2 i.v. over 24 h). The patient’s normal initial MTX clearance rate (107 ml/min/m2) was consistent with his undetectable plasma level of MTX on day 9 after the infusion. His plasma MTX concentration then gradually increased as his renal function declined, reaching a peak of 0.72 μM on day 15. This unusual finding of an undetectable plasma MTX concentration that subsequently rose to persistent, potentially toxic levels was explained only by a pharmacokinetic model that accounted both for a third space at the time of treatment and for the subsequent decrease in the systemic elimination rate. Therefore, the finding of a physiologic third space during MTX administration combined with the detection of renal dysfunction in the following weeks should be an indication for prolonged therapeutic drug monitoring.
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References
Chan H, Evans WE, Pratt CB (1977) Recovery from toxicity associated with high-dose methotrexate: prognostic factors. Cancer Treat Rep 61:797
D’Argenio DZ, Schumitzky A (1997) ADAPT II user’s guide: pharmacokinetic/pharmacodynamic systems analysis software. Biomedical Simulations Resource, Los Angeles
Evans WE, Pratt CB (1978) Effect of pleural effusion on high-dose methotrexate kinetics. Clin Pharmacol Ther 23:68
Li J, Gwilt P (2002) The effect of malignant effusions on methotrexate disposition. Cancer Chemother Pharmacol 50:373
Masson E, Relling MV, Synold TW, Liu Q, Schuetz JD, Sandlund JT, Pui CH, Evans WE (1996) Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. A rationale for high-dose methotrexate. J Clin Invest 97:73
Panetta JC, Yanishevski Y, Pui CH, Sandlund JT, Rubnitz J, Rivera GK, Ribeiro R, Evans WE, Relling MV (2002) A mathematical model of in vivo methotrexate accumulation in acute lymphoblastic leukemia. Cancer Chemother Pharmacol 50:419
Synold TW, Relling MV, Boyett JM, Rivera GK, Sandlund JT, Mahmoud H, Crist WM, Pui CH, Evans WE (1994) Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. J Clin Invest 94:1996
Wan SH, Huffman DH, Azarnoff DL, Stephens R, Hoogstraten B (1974) Effect of route of administration and effusions on methotrexate pharmacokinetics. Cancer Res 34:3487
Acknowledgements
Supported by Cancer Center CORE grant CA21765 and grant CA78224 from the National Institutes of Health, by a Center of Excellence grant from the State of Tennessee, and by the American Lebanese Syrian Associated Charities (ALSAC). C.-H. Pui is the American Cancer Society FM Kirby Clinical Research Professor.
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Pauley, J.L., Panetta, J.C., Schmidt, J. et al. Late-onset delayed excretion of methotrexate. Cancer Chemother Pharmacol 54, 146–152 (2004). https://doi.org/10.1007/s00280-004-0797-y
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DOI: https://doi.org/10.1007/s00280-004-0797-y