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Cytotoxicity of Dimethylacetamide and Pharmacokinetics in Children Receiving Intravenous Busulfan

Georg Hempel, Doris Oechtering, Claudia Lanvers-Kaminsky, Thomas Klingebiel, Josef Vormoor, Bernd Gruhn, Joachim Boos

From the Klinik und Poliklinik für Kinder und Jugendmedizin, Pädiatrische Hämatologie/Onkologie; Institut für Pharmazeutische and Medizinische Chemie der Universität Münster; Koordinierungszentrum Klinische Studien, Münster; Klinik für Kinderheilkunde III, Pädiatrische Hämatologie und Onkologie, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt; Universitätsklinikum Jena, Klinik für Kinder und Jugendmedizin, Allgemeine Pädiatrie, Hämatologie, Onkologie und Immunologie, Jena, Germany; and Newcastle University, Northern Institute for Cancer Research, Newcastle upon Tyne, United Kingdom

Address reprint requests to Georg Hempel, PD Dr.rer.nat, Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Klinische Pharmazie-Hittorfstr. 58-62, 48149 Muenster, Germany; e-mail: hempege{at}uni-muenster.de

Purpose To assess the cytotoxicity and the exposure of N,N-dimethylacetamide (DMA) in children during high-dose therapy with an intravenous (IV) formulation of busulfan containing the potentially hepatotoxic and neurotoxic DMA as a solvent.

Patients and Methods Eighteen children aged 0.9 to 17.3 years (median age, 4.0 years) received IV busulfan in 15 doses of 0.7 to 1.0 mg/kg busulfan containing overall DMA amounts of between 5 mmol (437 mg) and 70.5 mmol (6,142 mg) per dose. Plasma concentrations of DMA and busulfan were quantified and analyzed using nonlinear mixed-effects modeling. Four different leukemic cell lines were incubated with DMA, and cytotoxicity was assessed in comparison with busulfan as well as in a combination reflecting the ratio in the formulation.

Results Maximal plasma concentrations of DMA up to 3.09 mmol/L were observed. No accumulation of the solvent occurred. Instead, the trough levels decreased over the 4 treatment days. The population pharmacokinetic analysis revealed a clearance of 86.9 mL h^–1 kg^–1 ± 27% that increased to 298 mL h^–1 kg^–1 on the fourth day and a volume of distribution of 469 mL kg ± 22% (population mean ± interindividual variability). DMA volume of distribution correlated with the volume of distribution of busulfan. The cytotoxicity of DMA in vitro was 3 orders of magnitude lower than that of busulfan. No synergism was observed.

Conclusion The lack of accumulation of DMA confirms that there is no safety concern related to the DMA content in this IV busulfan formulation. The contribution of DMA to the antileukemic effect of the formulation seems to be limited.

Supported in part by Grants No. 01EC9801 and 01GG9846 from the German Federal Department of Research and Technology. Elternverein Viersen provided financial support for the liquid chromatography-mass spectrometry instrument.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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