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The distribution of ifosfamide (IF) and its metabolites 2-dechloroethylifosfamide (2DCE), 3-dechloroethylifosfamide (3DCE), 4-hydroxyifosfamide (4OHIF) and ifosforamide mustard (IFM) between plasma and erythrocytes was examined in vitro and in vivo. In vitro distribution was investigated by incubating blood with various concentrations of IF and its metabolites. In vivo distribution of IF, 2DCE, 3DCE and 4OHIF was determined in 7 patients receiving 9 g/m²/72 h intravenous continuous IF infusion. In vitro distribution equilibrium between erythrocytes and plasma was obtained quickly after drug addition. Mean (±sem) in vitro and in vivo erythrocyte (e)–plasma (p) partition coefficients (Pe/p) were 0.75±0.01 and 0.81±0.03, 0.62±0.09 and 0.73±0.05, 0.76±0.10 and 0.93±0.05 and 1.38±0.04 and 0.98±0.09 for IF, 2DCE, 3DCE and 4OHIF, respectively. These ratios were independent of concentration and unaltered with time. The ratios of the area under the erythrocyte and plasma concentration--time curves (AUCe/p) were 0.96±0.03, 0.87±0.07, 0.98±0.06 and 1.34±0.39, respectively. A time- and concentration-dependent distribution--equilibrium phenomenon was observed with the relative hydrophilic IFM. It is concluded that IF and metabolites rapidly reach distribution equilibrium between erythrocytes and plasma; the process is slower for IFM. Drug distribution to the erythrocyte fraction ranged from about 38% for 2DCE to 58% for 4OHIF, and was stable over a wide range of clinically relevant concentrations. A strong parallelism in the erythrocyte and plasma concentration profiles was observed for all compounds. Thus, pharmacokinetic assessment using only plasma sampling yields direct and accurate insights into the whole blood kinetics of IF and metabolites and may be used for pharmacokinetic–pharmacodynamic studies. Copyright © 2001 John Wiley & Sons, Ltd.

The distribution of ifosfamide (IF) and its metabolites 2‐dechloroethylifosfamide (2DCE), 3‐dechloroethylifosfamide (3DCE), 4‐hydroxyifosfamide (4OHIF) and ifosforamide mustard (IFM) between plasma and erythrocytes was examined in vitroand in vivo. In vitrodistribution was investigated by incubating blood with various concentrations of IF and its metabolites. In vivodistribution of IF, 2DCE, 3DCE and 4OHIF was determined in 7 patients receiving 9 g/m2/72 h intravenous continuous IF infusion. In vitrodistribution equilibrium between erythrocytes and plasma was obtained quickly after drug addition. Mean (±sem) in vitroand in vivoerythrocyte (e)–plasma (p) partition coefficients (Pe/p) were 0.75±0.01 and 0.81±0.03, 0.62±0.09 and 0.73±0.05, 0.76±0.10 and 0.93±0.05 and 1.38±0.04 and 0.98±0.09 for IF, 2DCE, 3DCE and 4OHIF, respectively. These ratios were independent of concentration and unaltered with time. The ratios of the area under the erythrocyte and plasma concentration‐‐time curves (AUCe/p) were 0.96±0.03, 0.87±0.07, 0.98±0.06 and 1.34±0.39, respectively. A time‐ and concentration‐dependent distribution‐‐equilibrium phenomenon was observed with the relative hydrophilic IFM. It is concluded that IF and metabolites rapidly reach distribution equilibrium between erythrocytes and plasma; the process is slower for IFM. Drug distribution to the erythrocyte fraction ranged from about 38% for 2DCE to 58% for 4OHIF, and was stable over a wide range of clinically relevant concentrations. A strong parallelism in the erythrocyte and plasma concentration profiles was observed for all compounds. Thus, pharmacokinetic assessment using only plasma sampling yields direct and accurate insights into the whole blood kinetics of IF and metabolites and may be used for pharmacokinetic–pharmacodynamic studies. Copyright © 2001 John Wiley & Sons, Ltd.

Experimental and clinical studies on ifosfamide indicate that fractionated treatment regimens have a higher efficacy compared to a single short-term infusion. In addition, protracted continuous infusion, in general, is often less toxic without loss of antitumour activity. To study the toxicity of a 10-day continuous infusion at increasing dosages of ifosfamide and mesna, 24 patients with a variety of advanced cancers (colon 10, pancreas 5, adenocarcinoma with unknown primary 5, and 4 others) received a total of 60 cycles (range 1–6 cycles, median 2) at 3 to 4 week intervals. The ifosfamide and mesna doses ranged from 654 mgm-2 day-1 to 1562 mgm-2 day-1 for a total of ten doses. Twenty-two patients were chemotherapynaive. Pharmacia-Deltec CADD-1 pumps and Port-a-Cath implantable venous access devices were used. The dose-limiting toxicity was leucopenia without thrombocytopenia. At a dose of 1300 mgm-2 day-1 in 30% of the cycles in 7 patients leucopenia of WHO grades 3 and 4 was observed, while at higher dosages this percentage increased to 73%. Haemoglobin values usually decreased during the infusion with a mean of 1 mmol/l (range 0.3–2.5 mmol/l), frequently with partial or full recovery by the next cycle. The next most disturbing side-effect was fatigue (50% of patients WHO grades 2 and 3), and nausea and vomiting requiring drug treatment in 75% of patients. Renal failure and haematuria did not occur. There were two catheter-related complications: thrombosis (1 patient) and mechanical obstruction (1 patient). One patient developed severe encephalopathy at day 6 (total dose 18 g ifosfamide) with complete recovery after cessation of the infusion. In summary, a tolerable ifosfamide dose using this regimen in this previously largely untreated patient group appears to be 1200–1300 mgm-2 day-1 for 10 days. Fatigue is a frequent complaint and might be explained as a kind of neurotoxicity. The treatment can be administered to outpatients.

Metastatic Ewing's sarcoma has generally a fatal outcome. Patients with bone metastases cannot be cured by conventional treatment and only 10% of patients with pulmonary disease have a considerable diseasefree survival (DFS). From 1990 six patients with metastatic Ewing's sarcoma have been treated in Leiden Univ. Hospital with HDC, followed by either bone marrow and/or peripheral stemcell rescue (SCR). Three of them suffered from recurrent Ewing's sarcoma, the other three had metastases at primary presentation.Pat. characteristics: 5 × male, one female. Mean age: 23 yrs. Localisation of primary tumor: rib 1 ×, vertebra 1 ×, scapula 2 ×, pelvis 2×. Metastases: bone 2×, lung 4×, lhn 2×. Induction treatment: VP16-Ifosfamide 4×, CDDP 2×. HDC: VP-16, Melphalan, Carboplatin 4×, VP-16-Melphalan 2×. TBI 1 ×. Four patients got 2 cycles of HDC; bone lesions were irradiated.