Saturable metabolism of continuous high-dose ifosfamide with Mesna and GM-CSF: A pharmacokinetic study in advanced sarcoma patients

Background: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide/mesna +/- GM-CSF administered by a fiv e-day continuous infusion at a total ifosfamide dose of 12-18 g/m(2) in adu lt patients with advanced sarcomas. Patients and methods: Between January 1991 and October 1992 32 patients wit h advanced or metastatic sarcoma were entered the study. Twenty-seven patie nts were pretreated including twenty-three with prior ifosfamide at less th an 8 g/m(2) total dose/cycle. In 25 patients (27 cycles) extensive pharmaco kinetic analyses were performed. Results: The area under the plasma concentration-time curve (AUC) for ifosf amide increased linearly with dose while the AUC's of the metabolites measu red in plasma by thin-layer chromatography did not increase with dose, part icularly that of the active metabolite isophosphoramide mustard. Furthermor e the AUC of the inactive carboxymetabolite did not increase with dose. Int erpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosuppression at 18 g/m(2) total dose with grade 4 neutrop enia in five of six patients and grade 4 thrombocytopenia in four of six pa tients. Therefore the maximum tolerated dose was considered to be 18 g/m(2) total dose. There was one CR and eleven PR in twenty-nine evaluable patien ts (overall response rate 41%). Conclusion: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of th e parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g /m(2) per cycle appear to result in a relative decrease of the active metab olite isophosphoramide mustard. These data suggest a dose-dependent saturat ion or even inhibition of ifosfamide metabolism by increasing high dose ifo sfamide and suggest the need for further metabolic studies.