Skip to main content
SpringerLink
Log in

Age-Dependent Pharmacokinetics of Doxorubicin in Children with Cancer

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

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.

Methods

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.

Results

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.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. van Dalen EC, Raphael MF, Caron HN, Kremer LC. Treatment including anthracyclines versus treatment not including anthracyclines for childhood cancer. Cochrane Database Syst Rev. 2014;9:CD006647.

    PubMed  Google Scholar 

  2. Eksborg S, Strandler HS, Edsmyr F, Naslund I, Tahvanainen P. Pharmacokinetic study of i.v. infusions of adriamycin. Eur J Clin Pharmacol. 1985;28(2):205–12.

    Article  CAS  PubMed  Google Scholar 

  3. Blum RH, Carter SK. Adriamycin. A new anticancer drug with significant clinical activity. Ann Intern Med. 1974;80(2):249–59.

    Article  CAS  PubMed  Google Scholar 

  4. Olson RD, Mushlin PS, Brenner DE, Fleischer S, Cusack BJ, Chang BK, et al. Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proc Natl Acad Sci USA. 1988;85(10):3585–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Robert J, Bui NB, Vrignaud P. Pharmacokinetics of doxorubicin in sarcoma patients. Eur J Clin Pharmacol. 1987;31(6):695–9.

    Article  CAS  PubMed  Google Scholar 

  6. Rodvold KA, Rushing DA, Tewksbury DA. Doxorubicin clearance in the obese. J Clin Oncol. 1988;6(8):1321–7.

    CAS  PubMed  Google Scholar 

  7. Piscitelli SC, Rodvold KA, Rushing DA, Tewksbury DA. Pharmacokinetics and pharmacodynamics of doxorubicin in patients with small cell lung cancer. Clin Pharmacol Ther. 1993;53(5):555–61.

    Article  CAS  PubMed  Google Scholar 

  8. Ryu RJ, Eyal S, Kaplan HG, Akbarzadeh A, Hays K, Puhl K, et al. Pharmacokinetics of doxorubicin in pregnant women. Cancer Chemother Pharmacol. 2014;73(4):789–97.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. McLeod HL, Relling MV, Crom WR, Silverstein K, Groom S, Rodman JH, et al. Disposition of antineoplastic agents in the very young child. Br J Cancer Suppl. 1992;18:S23–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Palle J, Frost BM, Peterson C, Gustafsson G, Hellebostad M, Kanerva J, et al. Doxorubicin pharmacokinetics is correlated to the effect of induction therapy in children with acute myeloid leukemia. Anticancer Drugs. 2006;17(4):385–92.

    Article  CAS  PubMed  Google Scholar 

  11. Frost BM, Eksborg S, Bjork O, Abrahamsson J, Behrendtz M, Castor A, et al. Pharmacokinetics of doxorubicin in children with acute lymphoblastic leukemia: multi-institutional collaborative study. Med Pediatr Oncol. 2002;38(5):329–37.

    Article  PubMed  Google Scholar 

  12. Hempel G, Flege S, Wurthwein G, Boos J. Peak plasma concentrations of doxorubicin in children with acute lymphoblastic leukemia or non-Hodgkin lymphoma. Cancer Chemother Pharmacol. 2002;49(2):133–41.

    Article  CAS  PubMed  Google Scholar 

  13. Thompson PA, Rosner GL, Matthay KK, Moore TB, Bomgaars LR, Ellis KJ, et al. Impact of body composition on pharmacokinetics of doxorubicin in children: a Glaser Pediatric Research Network study. Cancer Chemother Pharmacol. 2009;64(2):243–51.

    Article  CAS  PubMed  Google Scholar 

  14. Barry E, Alvarez JA, Scully RE, Miller TL, Lipshultz SE. Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management. Expert Opin Pharmacother. 2007;8(8):1039–58.

    Article  CAS  PubMed  Google Scholar 

  15. Hempel G, Schulze-Westhoff P, Flege S, Laubrock N, Boos J. Therapeutic drug monitoring of doxorubicin in paediatric oncology using capillary electrophoresis. Electrophoresis. 1998;19(16–17):2939–43.

    Article  CAS  PubMed  Google Scholar 

  16. Maudens KE, Stove CP, Cocquyt VF, Denys H, Lambert WE. Development and validation of a liquid chromatographic method for the simultaneous determination of four anthracyclines and their respective 13-S-dihydro metabolites in plasma and saliva. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877(30):3907–15.

    Article  CAS  PubMed  Google Scholar 

  17. Kontny NE, Hempel G, Boos J, Boddy AV, Krischke M. Minimization of the preanalytical error in plasma samples for pharmacokinetic analyses and therapeutic drug monitoring: using doxorubicin as an example. Ther Drug Monit. 2011;33(6):766–71.

    Article  CAS  PubMed  Google Scholar 

  18. Beal SSL, Boekmann A, Bauer RJ. NONMEM’s user’s guides. Ellicott City: ICON Development Solutions; 2009.

    Google Scholar 

  19. R_Core_Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2014.

    Google Scholar 

  20. Keizer RJ, van Benten M, Beijnen JH, Schellens JH, Huitema AD. Pirana and PCluster: a modeling environment and cluster infrastructure for NONMEM. Comput Methods Programs Biomed. 2011;101(1):72–9.

    Article  PubMed  Google Scholar 

  21. Lindbom L, Pihlgren P, Jonsson EN. PsN-Toolkit: a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed. 2005;79(3):241–57.

    Article  PubMed  Google Scholar 

  22. Jonsson EN, Karlsson MO. Xpose: an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed. 1999;58(1):51–64.

    Article  CAS  PubMed  Google Scholar 

  23. IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk: IBM Corp.

  24. Hempel G, Kontny NE. Pharmacokinetic analysis report for EPOC-MS-001-Doxo: interim analysis, Version V 1.3. 2012. p 13–58.

  25. Callies S, de Alwis DP, Wright JG, Sandler A, Burgess M, Aarons L. A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979). Cancer Chemother Pharmacol. 2003;51(2):107–18.

    CAS  PubMed  Google Scholar 

  26. Wilde S, Jetter A, Rietbrock S, Kasel D, Engert A, Josting A, et al. Population pharmacokinetics of the BEACOPP polychemotherapy regimen in Hodgkin’s lymphoma and its effect on myelotoxicity. Clin Pharmacokinet. 2007;46(4):319–33.

    Article  CAS  PubMed  Google Scholar 

  27. Kontny NE, Wurthwein G, Joachim B, Boddy AV, Krischke M, Fuhr U, et al. Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years. Cancer Chemother Pharmacol. 2013;71(3):749–63.

    Article  CAS  PubMed  Google Scholar 

  28. Blanco JG, Sun CL, Landier W, Chen L, Esparza-Duran D, Leisenring W, et al. Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(13):1415–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Lal S, Mahajan A, Chen WN, Chowbay B. Pharmacogenetics of target genes across doxorubicin disposition pathway: a review. Curr Drug Metab. 2010;11(1):115–28 (BSP/CDM/E-Pub/00049 [pii]).

    Article  CAS  PubMed  Google Scholar 

  30. Fagerholm R, Hofstetter B, Tommiska J, Aaltonen K, Vrtel R, Syrjakoski K, et al. NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer. Nat Genet. 2008;40(7):844–53.

    Article  CAS  PubMed  Google Scholar 

  31. Anderson BJ, Holford NH. Tips and traps analyzing pediatric PK data. Paediatr Anaesth. 2011;21(3):222–37.

    Article  PubMed  Google Scholar 

  32. Joerger M. Covariate pharmacokinetic model building in oncology and its potential clinical relevance. AAPS J. 2012;14(1):119–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Wang DD, Zhang S. Standardized visual predictive check versus visual predictive check for model evaluation. J Clin Pharmacol. 2012;52(1):39–54.

    Article  PubMed  Google Scholar 

  34. Thompson P, Wheeler HE, Delaney SM, Lorier R, Broeckel U, Devidas M, et al. Pharmacokinetics and pharmacogenomics of daunorubicin in children: a report from the Children’s Oncology Group. Cancer Chemother Pharmacol. 2014;74(4):831–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Hempel G, Relling MV, de Rossi G, Stary J, De Lorenzo P, Valsecchi MG, et al. Pharmacokinetics of daunorubicin and daunorubicinol in infants with leukemia treated in the interfant 99 protocol. Pediatr Blood Cancer. 2010;54(3):355–60.

    Article  PubMed  Google Scholar 

  36. Wong AL, Seng KY, Ong EM, Wang LZ, Oscar H, Cordero MT, et al. Body fat composition impacts the hematologic toxicities and pharmacokinetics of doxorubicin in Asian breast cancer patients. Breast Cancer Res Treat. 2014;144(1):143–52.

    Article  CAS  PubMed  Google Scholar 

  37. Lipshultz SE, Adams MJ. Cardiotoxicity after childhood cancer: beginning with the end in mind. J Clin Oncol. 2010;28(8):1276–81.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Author information

Author notes

  1. Alan V. Boddy

    Present address: Faculty of Pharmacy, University of Sydney, Sydney, NSW, 2006, Australia

Authors and Affiliations

  1. Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Muenster, Corrensstraße 48, 48149, Muenster, Germany

    Swantje Völler, Nina E. Kontny & Georg Hempel

  2. University Hospital Muenster, Paediatric Haematology and Oncology, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany

    Joachim Boos

  3. University Hospital Muenster, Centre for Clinical Trials, ZKS Muenster (BMBF 01KN1105), Von-Esmarch-Straße 62, 48149, Muenster, Germany

    Miriam Krischke & Gudrun Würthwein

  4. Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK

    Alan V. Boddy

Authors
  1. Swantje Völler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joachim Boos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miriam Krischke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gudrun Würthwein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nina E. Kontny
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alan V. Boddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Georg Hempel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Georg Hempel.

Additional information

A. V. Boddy and G. Hempel contributed equally.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Völler, S., Boos, J., Krischke, M. et al. Age-Dependent Pharmacokinetics of Doxorubicin in Children with Cancer. Clin Pharmacokinet 54, 1139–1149 (2015). https://doi.org/10.1007/s40262-015-0272-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-015-0272-4

Keywords

Search

Navigation