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Cytotoxicity of dimethylacetamide and pharmacokinetics in children receiving intravenous busulfan

Lookup NU author(s): Professor Hermann Josef Vormoor


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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.

Publication metadata

Author(s): Hempel, G., Oechtering, D., Lanvers-Kaminsky, C., Klingebiel, T., Vormoor, J., Gruhn, B., Boos, J.

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Oncology

Year: 2007

Volume: 25

Issue: 13

Pages: 1772-1778

ISSN (print): 0732-183X

ISSN (electronic): 1527-7755


DOI: 10.1200/JCO.2006.08.8807


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