Concentrations of methotrexate have been determined in the serum and cerebrospinal fluid after 406 infusions of methotrexate to 58 children with acute lymphoblastic leukemia. The dose of methotrexate varied between 500 mg/m2 and 33 600 mg/m2. Pharmacokinetic analysis of the data has been carried out. The effect of dose, age, and number of treatments on steady-state concentration, serum half-life, cerebrospinal fluid (CSF) serum distribution ratio, volume of distribution, systemic clearance of meth-otrexate was examined. The elevation of dose resulted in a nonproportional increase of the steady-state concentrations both in serum and CSF. The great inpatient and interpatient variations of steady-state concentrations caused only statistically not significant differences in the parameters of different subgroups of dosages. Correlation was found between concentrations of methotrexate in serum and CSF. One to 4 years old children were found to have lower steady-state concentrations of methotrexate in the serum and CSF, greater volume of distribution and faster clearence of the drug. Dose-dependency and age-dependency of methotrexate pharmacokinetics has been concluded. Cuncer 60513.1987. ETHOTREXATE (MTX), the most widely used an-M timetabolite in cancer chemotherapy, has a role in the treatment of such diverse malignancies as acute lymphoblastic leukemia, osteogenic sarcoma, non-Hodgkin's lymphomas, choriocarcinomas, head and neck cancer, breast cancer, cancer of the lung, or brain tumors.' It has three such features that contributed to its distinguished place in the history of cancer chemother-apy: (1) it is the only cytostatic drug that has an antidote (folinic acid) in clinical use; (2) it has the widest dose-range of application (3 mg-33,600 mg/m2); and (3) it is the only anticancer agent for that a bedside monitoring of concentrations is a clinical routine. A great number of reports have been published during the last 38 years on the pharmacokinetics and clinical use of MTX. However, these are difficult to compare because of different dose and time schedules of the administration of the drug and different time schedules of sampling for determination of MTX levels. The sensitivity and specificity of the methods used for the measurement of MTX concentrations are different as well. In this article we present our pharmacokinetic observations on 406 infusions of MTX to 58 children with acute lymphoblastic leukemia (ALL), in a dose range of 0.5 g to 33.6 g/m2. All the treatments have been given in the same hospital , with the same standard routine of administration of the drug as a part of the same basic concept of the chemotherapy of ALL. The determinations of MTX concentrations have been carried out by the same method and even by the same laboratory assistents during a period of 8 years. To our knowledge, no publications covering the whole dose range of 0.5 g to 33.6 g/m2 are so far available.
The prognostic value of systemic clearance of methotrexate (MTX) has been evaluated in 58 children with acute lymphoblastic leukemia, receiving altogether 380 MTX infusions in a dose range of 0.5 to 33.6 g/m2. The linear regression analysis of dose-steady state concentration relationship revealed that relapsed children had significantly lower steady state concentration of MTX (faster systemic clearance) than those who remained in continuous complete remission (CCR), whatever dosage of the drug was given. Relapsed children (n = 25) had a systemic clearance of MTX 122.5 +/- 55.5 ml/minute/m2 versus 71.8 +/- 25.8 ml/minute/m2 found in the CCR patients (n = 33) when the dosage of MTX was 0.5 to 1.0 g/m2. When the dose was 6.0 to 8.0 g/m2 the clearance values were 93.27 +/- 32.6 versus 61.8 +/- 24.5 ml/minute/m2, respectively. The differences are statistically significant (P less than 0.001). In 16 of 25 relapsed patients (64%) an increase of the systemic clearance has been observed during the consecutive treatments, but only 4/33 CCR patients (12%) has expressed such a phenomenon. The dose-independent prognostic relevance of systemic clearance of MTX as a possible sign of resistance to MTX is concluded.
During the period 1979 to 1992 we treated 141 children for various malignant diseases with protocols including methotrexate (MTX) infusions in doses ranging from 0.5 to 33.6 g/m2. During a total of 922 courses, there were no fatal complications associated with MTX treatment. Serum MTX concentration and pharmacokinetic data were monitored continuously during the infusions. In this study, we evaluated the occurrence of serious untoward reactions to MTX infusions. Impaired renal function with delayed drug elimination was seen in seven patients, all boys, especially after short infusion times. All recovered completely without any serious clinical symptoms. In three leukemia patients who later died from resistant disease, we observed late neurological disturbances and computer tomography (CT) brain scan abnormalities. Pharmacokinetic data from the patients with complications are described and confirm that serial MTX concentration monitoring is the most important early indicator of renal toxicity.
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