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The pharmacokinetics of alkylating activity were studied in 17 children treated i.v. with ifosfamide (IF) at 3 g/m2 as a 1-h infusion for 2 consecutive days every 3 weeks, with mesna as a uroprotector. Two patients were treated for a newly diagnosed rhabdomyosarcoma according to the current SIOP (International Society of Pediatric Oncology) protocol. The other 15 patients were treated in a phase II study and presented with one of the following malignancies in relapse: neuroblastoma (7), osteosarcoma (3), soft tissue sarcoma (2), Wilms' tumor (1), non-Hodgkin's lymphoma (1), and acute lymphoblastic leukemia (1). Plasma alkylating activity levels determined by using 4(4'-nitro-benzyl)-pyridine showed considerable inter-individual and intercyclic variations and decreased biphasically, with mean alpha and beta half-lives of 60 min and 6-7 h, respectively. Probably as a result of liver mixed-function oxidase induction, on the 2nd day of treatment the terminal half-lives were shorter, the plasma exposures were lower, and the mean plasma clearances were higher. Renal excretion was almost complete after 24 h, accounting for a mean of 19% of the injected dose. The CSF alkylating activity levels, obtained in four children, were always lower than the plasma levels and ranged from 8 to 51 micrograms/ml, with a mean CSF/plasma ratio of 0.53 +/- 0.23 during the first 12 h. We conclude that IF alkylating activity was biphasically cleared from the plasma, with significant interindividual and intercyclic variability, that the renal contribution to the clearance was low, and that high levels of CSF alkylating activity could possibly contribute to the CNS toxic side effects observed in pediatric patients treated with high-dose IF/mesna.

Nine children with poor-prognosis malignancies--seven with advanced neuroblastoma and two with metastatic Ewing's sarcoma--were given high doses of melphalan (HDM), 150 mg/m2 (3 patients) and 180 mg/m2 (6 patients), as a 'late intensification' agent combined with noncryopreserved autologous bone marrow transplants. Melphalan levels in the plasma decreased biphasically, with mean half-lives of 6.6 min and 3.0 h. At the time of marrow reinfusion (12-21 h after HDM) the melphalan plasma level was generally below 0.1 microgram/ml. The renal contribution to melphalan clearance was low, a mean of 5.8% of the injected dose being found in patients' urine over the 12 h following HDM administration. No significant difference was seen in pharmacokinetic parameters between patients undergoing and not undergoing forced diuresis.