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Population pharmacokinetics of dimethylacetamide in children during standard and once-daily IV busulfan administration

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Abstract

Purpose

N,N-dimethylacetamide (DMA) is administered to children during high-dose chemotherapy as a solubilizer with the intravenous formulation of busulfan (Busilvex®). DMA has shown liver toxicity in rats. However, little is known regarding its pharmacokinetics (PK) in humans. The aim of this analysis was to compare the PK of DMA after a once-daily dose of Busilvex® with the standard scheme consisting of 3–4 administrations per day in children.

Methods

Out of 42 children, aged 0.1–18.9 years, receiving Busilvex®, 18 children received the first dose as a loading dose, giving a double dose of 1.4–2.0 mg/kg over a 4 h infusion followed by 15 doses of 0.7–1.0 mg/kg as 2 h infusions every 6 h. The other 24 children received Busilvex® as 3 h infusions once-daily for 4 consecutive days with a targeted busulfan AUC of 4,263 μM*min. Using NONMEM™ plasma, concentration–time data were analyzed. Assuming an increase in clearance overtime as found in our previous investigation, separate time factors for the two different dosing schedules included in the dataset were tested.

Results

A one-compartment model with clearance increasing over time described the DMA kinetics sufficiently. Peak plasma concentrations of DMA, up to 3.09 mmoL/L (median 0.75 mmoL/L) for the current licensed dose regimen and up to 8.77 mmoL/L (median 3 mmoL/L) for the once-daily application, were observed. The examined increase in clearance was found to be 58 mL/h/kg and 6.1 mL/h/kg per day for the current licensed and the once-daily dose regimen, respectively.

Conclusion

N,N-dimethylacetamide as solvent of lipophilic drugs such as busulfan has a linear PK in children of all ages using a dose split into one or four administrations per day. The rapid clearance with different dosing in patients of different body weights indicates that it is safe to use DMA in children in both a once and four times daily regimen.

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Conflict of interest

Along with the principal study investigators, Mirjam N. Trame, Joachim Boos and Georg Hempel who act as the guarantors, all other investigators, namely Imke H. Bartelink and Jaap J. Boelens had full access to the data and took part in the design, execution and data analysis, and in writing the report. None of the authors listed have financial or personal relationships with other people or organizations that inappropriately influence their actions.

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Authors and Affiliations

  1. Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Münster, Münster, Germany

    Mirjam N. Trame & Georg Hempel

  2. Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida, 6550 Sanger Road, Office 471, Orlando, FL, 32827, USA

    Mirjam N. Trame

  3. Department of Hematology, Immunology and Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands

    Imke H. Bartelink & Jaap J. Boelens

  4. Department of Pediatric Hematology and Oncology, University Children’s Hospital Münster, Münster, Germany

    Joachim Boos & Georg Hempel

  5. Department of Bioengineering and Therapeutic Science, University of San Francisco, San Francisco, CA, USA

    Imke H. Bartelink

Authors
  1. Mirjam N. Trame
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  2. Imke H. Bartelink
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  3. Joachim Boos
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  4. Jaap J. Boelens
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  5. Georg Hempel
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Correspondence to Mirjam N. Trame.

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Trame, M.N., Bartelink, I.H., Boos, J. et al. Population pharmacokinetics of dimethylacetamide in children during standard and once-daily IV busulfan administration. Cancer Chemother Pharmacol 72, 1149–1155 (2013). https://doi.org/10.1007/s00280-013-2284-9

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  • DOI: https://doi.org/10.1007/s00280-013-2284-9

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