Dose-related increases in cerebrospinal fluid concentrations of methotrexate in a postoperative patient with glioblastoma

OBJECTIVE: To investigate the postoperative pharmacokinetics of methotrexate in the plasma and cerebrospinal fluid (CSF) in the space created by tumor removal of a patient with glioblastoma during hyperosmotic disruption of the blood-brain barrier (BBB) and intraarterial chemotherapy with a stepwise increase in the methotrexate dosage. CASE SUMMARY: A 30-year-old Japanese woman with glioblastoma received four courses of hyperosmotic disruption of the BBB and intraarterial chemotherapy with a combination of peplomycin, vindesine, nimustine, pirarubicin, and methotrexate. The patient was initially administered mannitol; anticancer drugs were then infused into the left internal carotid artery. Following the first, second, third, and fourth courses of treatment, methotrexate 350, 700, 1000, and 1500 mg, respectively, were administered for 30 minutes. Samples of blood and CSF from the space created by tumor removal were obtained. Methotrexate concentrations were measured by fluorescence polarization immunoassay and the pharmacokinetic parameters of methotrexate in plasma and CSF were estimated. RESULTS: The plasma concentration of methotrexate peaked at the end of drug infusion, then decreased in a biexponential decay manner during the remainder of the treatment period. The CSF concentration of methotrexate in the space created by tumor removal peaked two hours after drug administration, then monoexponentially decreased. Although the maximal CSF concentration of methotrexate in the space created by tumor removal was lower than that in the plasma, the CSF concentration of methotrexate in the space created by tumor removal exceeded that in the plasma six hours after drug infusion. The half-life of methotrexate in the CSF exceeded that in the plasma. The AUC for the plasma and CSF methotrexate concentration increased parallel with the methotrexate dosage. The mean CSF AUC of methotrexate was 59.4% of that found in plasma. CONCLUSIONS: The CSF AUC of methotrexate in the space created by tumor removal increased parallel with the methotrexate dosage during hyperosmotic disruption of the BBB and intraarterial chemotherapy.