Advertisement

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

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.

Keywords

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.

Notes

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.

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)

References

  1. 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.PubMedGoogle Scholar
  2. 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.CrossRefPubMedGoogle Scholar
  3. 3.
    Blum RH, Carter SK. Adriamycin. A new anticancer drug with significant clinical activity. Ann Intern Med. 1974;80(2):249–59.CrossRefPubMedGoogle Scholar
  4. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Robert J, Bui NB, Vrignaud P. Pharmacokinetics of doxorubicin in sarcoma patients. Eur J Clin Pharmacol. 1987;31(6):695–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Rodvold KA, Rushing DA, Tewksbury DA. Doxorubicin clearance in the obese. J Clin Oncol. 1988;6(8):1321–7.PubMedGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 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.PubMedCentralPubMedGoogle Scholar
  10. 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.CrossRefPubMedGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 18.
    Beal SSL, Boekmann A, Bauer RJ. NONMEM’s user’s guides. Ellicott City: ICON Development Solutions; 2009.Google Scholar
  19. 19.
    R_Core_Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2014.Google Scholar
  20. 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.CrossRefPubMedGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 23.
    IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk: IBM Corp.Google Scholar
  24. 24.
    Hempel G, Kontny NE. Pharmacokinetic analysis report for EPOC-MS-001-Doxo: interim analysis, Version V 1.3. 2012. p 13–58.Google Scholar
  25. 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.PubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedGoogle Scholar
  28. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 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]).CrossRefPubMedGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 31.
    Anderson BJ, Holford NH. Tips and traps analyzing pediatric PK data. Paediatr Anaesth. 2011;21(3):222–37.CrossRefPubMedGoogle Scholar
  32. 32.
    Joerger M. Covariate pharmacokinetic model building in oncology and its potential clinical relevance. AAPS J. 2012;14(1):119–32.PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Wang DD, Zhang S. Standardized visual predictive check versus visual predictive check for model evaluation. J Clin Pharmacol. 2012;52(1):39–54.CrossRefPubMedGoogle Scholar
  34. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 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.CrossRefPubMedGoogle Scholar
  36. 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.CrossRefPubMedGoogle Scholar
  37. 37.
    Lipshultz SE, Adams MJ. Cardiotoxicity after childhood cancer: beginning with the end in mind. J Clin Oncol. 2010;28(8):1276–81.CrossRefPubMedGoogle Scholar

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

Personalised recommendations