Iron Overload Exacerbates Busulfan-Melphalan Toxicity Through a Pharmacodynamic Interaction in Mice.

PURPOSE: Busulfan-melphalan high-dose chemotherapy followed by autologous stem cell transplantation is an essential consolidation treatment of high-risk neuroblastoma in children. Main treatment limitation is hepatic veno-occlusive disease, the most severe and frequent extra-hematological toxicity. This life threatening toxicity has been related to a drug interaction between busulfan and melphalan which might be increased by prior disturbance of iron homeostasis, i.e. an increased plasma ferritin level. METHODS: We performed an experimental study of busulfan and melphalan pharmacodynamic and pharmacokinetics in iron overloaded mice. RESULTS: Iron excess dramatically increased the toxicity of melphalan or busulfan melphalan combination in mice but it did not modify the clearance of either busulfan or melphalan. We show that prior busulfan treatment impairs the clearance of melphalan. This clearance alteration was exacerbated in iron overloaded mice demonstrating a pharmacokinetic interaction. Additionally, iron overload increased melphalan toxicity without altering its pharmacokinetics, suggesting a pharmacodynamic interaction between iron and melphalan. Based on iron homeostasis disturbance, we postulated that prior induction of ferritin, through Nrf2 activation after oxidative stress, may be associated with the alteration of melphalan metabolism. CONCLUSION: Iron overload increases melphalan and busulfan-melphalan toxicity through a pharmacodynamic interaction and reveals a pharmacokinetic drug interaction between busulfan and melphalan.

Stability of etoposide solutions in disposable infusion devices for day hospital cancer practices.

In a context of day hospital care of cancer patients, a protocol combining etoposide and carboplatin is used in paediatrics. Disposable infusion devices can be used to improve patient quality of life and to optimize nursing time. Stability data are available for carboplatin in these devices but not for etoposide. The aim of this study was to determine the stability of etoposide solutions in these devices by monitoring the changing etoposide concentration. To study the changing etoposide concentration, we investigated three different concentrations, each in two different solvents: sodium chloride (NaCl) 0.9 % and dextrose 5 %, in Intermate(®) disposable infusion devices. Quantitative analyses were performed by high-performance liquid chromatography coupled with ultraviolet (UV) detection on samples collected over a 24-h study period. The results showed that 100 mg/L etoposide solutions were stable for 24 h in NaCl 0.9 % and for 12 h in dextrose 5 %, whatever the temperature. The 400-mg/L solutions were stable for 24 h in both diluents, whatever the temperature, whereas the 600-mg/L solutions when diluted in NaCl 0.9 % and dextrose 5 % in water were stable for 8 and 6 h, respectively. We found that precipitation was the main phenomenon responsible for decreased etoposide concentrations. This study allowed us to conclude that etoposide solutions prepared in Intermate(®) infusion devices are stable for day hospital administration in paediatrics. It will also allow us to conduct a future clinical study that will focus on the medico-economic feasibility of this protocol and on the evaluation of patient and nurse satisfaction.