Clinical Pharmacokinetics

, Volume 54, Issue 11, pp 1139–1149 | Cite as

Age-Dependent Pharmacokinetics of Doxorubicin in Children with Cancer

  • Swantje Völler
  • Joachim Boos
  • Miriam Krischke
  • Gudrun Würthwein
  • Nina E. Kontny
  • Alan V. Boddy
  • Georg Hempel
Original Research Article


Background and Objective

Knowledge on the pharmacokinetics of doxorubicin, especially in children, is very limited with conflicting evidence concerning a possible age dependency in the pharmacokinetics. The aim of the current investigation was to assess, by using population pharmacokinetics, whether an age dependency in the clearance (CL) of doxorubicin exists.


Pharmacokinetic data of doxorubicin and its main metabolite doxorubicinol from 94 children (aged 0–18 years) from the EPOC-MS-001-Doxo trial were available. A population pharmacokinetic model was developed in NONMEM® 7.2.0.


A linear three-compartment model for doxorubicin, with one additional compartment for doxorubicinol, gave the best fit to the data. All model parameters were linearly scaled on body surface area. Including a power function of age as a covariate for CL led to a further improvement of the model. Variation in genes encoding for enzymes involved in the metabolism or active transport of doxorubicin had no influence on the pharmacokinetics. Estimates of CL were lower (26.6 L/h/m2 in children aged >3 years and 21.1 L/h/m2 in children aged ≤3 years, p = 0.0004) in children aged <3 years, compared with older children.


This is the first model to describe the pharmacokinetics of doxorubicin in children, with a specific focus on infants and children aged <3 years. The lower CL in younger children should be considered together with the pharmacodynamics, especially the cardiotoxicity, when selecting the dose for future protocols.


Doxorubicin Body Surface Area Population Pharmacokinetic Analysis Objective Function Value Carbonyl Reductase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We wish to thank all clinical investigators and clinical trials centres that participated in the EPOC-MS-001-Doxo trial. This trial and all accompanying research were funded by the European Community’s Seventh Framework Programme (FP7/2009-2013) under Grant Agreement No. 222910. Miriam Krischke and Gudrun Würthwein are supported by the German Federal Ministry of Research and Education (BMBF Grant No. 01KN1105). Joachim Boos served personally as a consultant and participated in advisory boards for the medac GmbH. In addition, there are institutional Grants and cooperation with medac GmbH—all related to asparaginase and/or pharmacovigilance. There is no conflict of interest concerning doxorubicin. Swantje Völler, Nina E. Kontny, Alan V. Boddy and Georg Hempel have no conflicts on interest to declare.

Supplementary material

40262_2015_272_MOESM1_ESM.pdf (153 kb)
Supplementary material 1 (PDF 153 kb)
40262_2015_272_MOESM2_ESM.pdf (87 kb)
Supplementary material 2 (PDF 87 kb)
40262_2015_272_MOESM3_ESM.pdf (180 kb)
Supplementary material 3 (PDF 180 kb)
40262_2015_272_MOESM4_ESM.pdf (121 kb)
Supplementary material 4 (PDF 121 kb)


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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Swantje Völler
    • 1
  • Joachim Boos
    • 2
  • Miriam Krischke
    • 3
  • Gudrun Würthwein
    • 3
  • Nina E. Kontny
    • 1
  • Alan V. Boddy
    • 4
    • 5
  • Georg Hempel
    • 1
  1. 1.Department of Pharmaceutical and Medical Chemistry, Clinical PharmacyUniversity of MuensterMuensterGermany
  2. 2.University Hospital Muenster, Paediatric Haematology and OncologyMuensterGermany
  3. 3.University Hospital Muenster, Centre for Clinical Trials, ZKS Muenster (BMBF 01KN1105)MuensterGermany
  4. 4.Northern Institute for Cancer Research, Medical School, Newcastle UniversityNewcastle upon TyneUK
  5. 5.Faculty of PharmacyUniversity of SydneySydneyAustralia

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