PHARMACOKINETICS, METABOLISM AND CLINICAL EFFECT OF IFOSFAMIDE IN BREAST-CANCER PATIENTS

Ifosfamide (IFO) at a dose of 5 g/m(2), was administered as a 24-h infusion to 15 patients with metastatic (12) or locally advanced (3) breast cancer (age range 33-59 years, median 46). Concurrent chemotherapy was doxorubicin (40 mg/m(2)) or epirubicin (60 mg/m(2)). Ifosfamide and its metabolites were measured in plasma and urine during and for 24 h after the infusion using a high performance thin layer chromatography (HPTLC) technique. Patients' haematological toxicity and biochemistry were monitored during treatment and patients were followed for up to 2 years after therapy. At the time of evaluation, 5 of the patients were alive, 2 of whom had not relapsed. A marked variation was observed in the pharmacokinetics and metabolism of ifosfamide in the evaluable patients. Clearance, volume of distribution and half-life of the drug were 3.48 +/- 0.88 l/h/m(2), 0.56 +/- 0.22 l/kg and 4.68 +/- 2.01 h, respectively. There was no apparent correlation between these pharmacokinetic variables and patient age, weight or renal function. AUCs of the ultimate alkylating species isophosphoramide mustard (IPM) varied over 6-fold, as did those of the inactivated metabolite carboxyifosfamide (CX). AUCs of dechloroethylated metabolites varied 4-fold (3 -dechloroethylifosfamide, 3-DCI) or 8-fold (2-D CI), while that of the parent compound varied only 2.5-fold. Variation in recovery of the metabolites in urine varied over an even wider range, total recovery varying from 17.5 to 81.8% of the dose administered. There was little apparent correlation between pharmacokinetic and metabolite parameters of IFO and haematological toxicity. However, there was a marked negative correlation between both progression-free interval and survival and the AUCs of the products of IFO activation (IPM and CX). In addition, the recovery of IPM in urine was higher in patients experiencing a partial response compared to those with progressive or stable disease. Recovery of dechloroethylated metabolites correlated positively with survival, if 1 poor prognosis patient was excluded. Although far from conclusive, these results give some insight into a possible mechanism of action of ifosfamide and indicate that some species other than IPM, as measured systemically, is responsible for the pharmacological effects of this drug.