Summary
Methotrexate (MTX) in serum was measured by RIA in 12 cancer patients receiving high doses of MTX (2 to 8 g/m2) in 6 hour infusions 69 treatments were studied. The peak serum level was proportional to the dose administered and was always greater than 10−4 M. 2 elimination phases were seen: the first had a mean half-life of 2.36 h and the second a mean half-life of 16.14 h. 24 hours after beginning the infusions there were very large variations in individual serum concentrations of MTX, from 2.4 10−6 M to 1.9 10−5 M by 24 h after 8 g/m2. To control these variations, a mathematical model for prediction of the individual pharmacokinetic pattern of a 6 hour-infusion of high-dose MTX by kinetic analysis of a low-test dose is proposed. A program was created for an Apple III computer using toxic and therapeutic serum levels of MTX selected by the clinician. The computer program is adaptable to any infused substance for variable infusion times, thus introducing new advances over existing methods.
Similar content being viewed by others
References
Bleyer WA (1978) The clinical pharmacology of methotrexate: new applications of an old drug. Cancer 10: 36–51
Blender RA, Zwelling LA, Doroshow JH (1978) Antineoplastic drugs: clinical pharmacology and therapeutic use. Drugs 16: 46–87
Pitman SN, Frei E (1976) Weekly methotrexate-calcium leucovorin rescue: effects of alkalinization on nephrotoxicity; pharmacokinetics in the CNS; and use in CNS non-Hodgkin's lymphoma. Cancer Treat Rep 61: 695–701
Frei E (1976) Methotrexate revisited. Med Pediatr Oncol 2: 227–241
Pinedo HM, Chabner BA (1977) Role of drug concentration, duration of exposure and endogenous metabolites in determining methotrexate cytotoxicity. Cancer Treat Rep 61: 709–715
Tattersall MHN, Parker LM, Pitman SW, Frei E (1975) Clinical pharmacology of high-dose methotrexate. Cancer Chemother Rep 6: 25–29
Stoller RG, Hande KR, Jacobs SA, Rosenberg SA, Chabner BA (1977) Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. N Engl J Med 297: 630–634
Niremberg A, Mosende C, Mehta BM, Gisolfi AL, Rosen G (1977) High dose methotrexate with C. F. rescue: Predictive value of serum methotrexate concentrations and corrective measures to avert toxicity. Cancer Treat Rep 61: 779–783
Isacoff WH, Morrisson PF, Aroesty J (1977) Pharmacokinetics of high-dose methotrexate with citrovorum factor rescue. Cancer Treat Rep 61: 1665–1674
Evans WE, Pratt CB, Taylor RH, Barker LF, Crom WR (1979) Pharmacokinetics monitoring of high-dose methotrexate. Cancer Chemother Pharmacol 3: 161–166
Favre R, Monjanel S, Alfonsi M, Pradoura JP, Bagarry-Liegey D, Clement S, Imbert AN, Lena N, Colonna D'Istria J, Cano JP, Carcassonne Y (1982) High-dose methotrexate: a clinical and pharmacokinetic evaluation. Cancer Chemother Pharmacol 9: 156–160
Crom WR, Taylor RH, Pratt CB (1981) Therapeutic use and serum concentration monitoring. In: Taylor WJ, Finn AL (eds) Individualizing Drug Therapy. Gross, Townsend and Frank, New York
Stoller RG, Kaplan HG, Cummings FJ, Calabresi P (1979) A clinical and pharmacological study of high-dose methotrexate with minimal leucovorin rescue. Cancer Res 39: 908–912
Cohen HJ, Jaffe N (1978) Pharmacokinetic and clinical studies of 24-h infusions of high-dose methotrexate. Cancer Chemother Pharmacol 1: 61–64
Goh TS, Wong KY, Lampkin B, O'Leary J, Gnarra D (1979) Evaluation of 24-hour infusion of high-dose methotrexate. Pharmacokinetics and toxicity. Cancer Chemother Pharmacol 3: 177–180
Monjanel S, Rigault JP, Cano JP, Carcassonne Y, Favre R (1979) High-dose methotrexate: preliminary evaluation of a pharmacokinetic approach. Cancer Chemother Pharmacol 3: 189–196
Bore P, Rahmani R, Cano JP, Just S, Barbet J (1984) Radioimmunoassays of 7-hydroxymethotrexate and methotrexate. Clin Chim Acta 141: 135–149
Cazin JL, Luyckx M (1984) Determination of pharmacokinetic parameters on Apple computer. Trends Pharmacol Sci 5: 411–413
Gibbons JD (1971) Nonparametric statistical inference. McGraw Hill, New York
Wang YM, Sutow WW, Romsdahl MH, Perez C (1979) Age-related pharmacokinetics of high-dose methotrexate in patients with osteosarcoma. Cancer Treat Rep 63: 405–410
Bratlid D, Moe PJ (1978) Pharmacokinetics of high-dose methotrexate treatment in children. Eur J Clin Pharmacol 14: 143–147
Pratt CB, Roberts D, Shanks E, Warmath EL (1975) Response, toxicity and pharmacokinetics of high-dose methotrexate with citrovorum factor rescue for children with osteosarcoma and other malignant tumors. Cancer Chemother Rep 6: 13–18
Stoller RG, Jacobs SA, Drake JC, Lutz RJ, Chabner BA (1975) Pharmacokinetics of methotrexate. Cancer Chemother Rep 6: 19–24
Huffman DH, Wan SH, Azarnoff DL (1973) Pharmacokinetics of methotrexate. Clin Pharmacol Ther 14: 572–579
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Luyckx, M., Cazin, J.L., Brunet, C. et al. Clinical pharmacokinetics of 6-hour infusion of high-dose methotrexate. Preliminary trial of monitoring high infusion doses. Eur J Clin Pharmacol 28, 457–462 (1985). https://doi.org/10.1007/BF00544367
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00544367