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

Mirjam N. Trame, Imke H. Bartelink, Joachim Boos, Jaap J. Boelens, Georg Hempel

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1149-1155
Number of pages7
JournalCancer chemotherapy and pharmacology
Volume72
Issue number5
DOIs
Publication statusPublished - Nov 2013

Keywords

  • Busulfan
  • Dimethylacetamide
  • Drug monitoring
  • Pediatrics
  • Population pharmacokinetics

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