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Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years

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Abstract

Purpose

The aim of the current investigation was to develop a population pharmacokinetic model for doxorubicin and doxorubicinol that could provide improved estimated values for the pharmacokinetic parameters clearance of doxorubicin, volume of distribution of the central compartment, clearance of doxorubicinol and volume of distribution of the metabolite compartment for adults and children older than 3 years. A further aim was to investigate the potential influence of the covariates body surface area, body weight, body height, age, body mass index, sex and lean body mass on the pharmacokinetic parameters.

Methods

Three different datasets, two containing data from adults and one containing data from adults and children, were merged and the combined dataset was analysed retrospectively. In total, the combined dataset contained 934 doxorubicin and 935 doxorubicinol plasma concentrations from 82 patients [64 adults and 18 children (<18 years)]. With this combined dataset, a population pharmacokinetic model was developed, using NONMEM® 7.2 and a predefined model-building strategy. Different structural models, error models and estimation methods were tested, and the inter-individual and the inter-occasion variability (variability between separate (two or three) doxorubicin infusions) were tested. Using a subset of 52 patients, the influence of different covariates on the pharmacokinetic parameters was investigated. The pharmacokinetic parameter estimates obtained from doxorubicin concentrations with the best model were fixed, and an additional compartment for doxorubicinol was added to the model. With the final model for both substances, a potential age dependency and body mass index dependency of the clearance of doxorubicin and doxorubicinol as well as of the volumes of distribution of the central and the metabolite compartment were evaluated.

Results

A four-compartment model best described the doxorubicin and doxorubicinol data of the combined dataset. This model included a proportional residual error model and an inter-individual variability on the clearance of doxorubicin, on the inter-compartmental clearances of the peripheral compartments, on the clearance of doxorubicinol and on the volumes of distribution of the central, one peripheral and the metabolite compartment. Furthermore, the body surface area as covariate on all pharmacokinetic parameters and an inter-occasion variability for the clearance of doxorubicin and the volume of distribution of the central compartment were incorporated in the model. For a patient with the body surface area of 1.8 m², the clearance of doxorubicin was 53.3 L/h (inter-individual variability 31 %, inter-occasion variability 13 %) and the volume of distribution of the central compartment was 17.7 L (inter-individual variability 19 %, inter-occasion variability 21 %), respectively. The residual variability of the model was 22 % for doxorubicin and 26 % for doxorubicinol. The clearance of doxorubicinol was estimated at 44 L/h (inter-individual variability 50 %) and the volume of distribution of the metabolite compartment at 1,150 L (inter-individual variability 57 %). The evaluation of a possible age dependency and body mass index dependency showed a trend to a smaller volume of distribution of the central compartment (normalised to the body surface area) and a higher volume of distribution of the metabolite compartment (normalised to the body weight) in younger patients.

Conclusions

A four-compartment NONMEM® model for doxorubicin and doxorubicinol adequately described the plasma concentrations in adults and children (>3 years). No pronounced effects of age on the clearance of doxorubicin or doxorubicinol were found, and the analysis did not support the modification of the dosing strategies presently used in children and adults.

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Abbreviations

CL:

Clearance

CWRES:

Conditional weighted residuals

dox’ol:

Doxorubicinol

h:

Hour

kg:

Kilogram

L:

Litre

min:

Minute

OFV:

Objective function value

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Acknowledgments

The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2009-2013) under grant agreement n° 222910. MK and GW are supported by the German Federal Ministry of Research and Education (BMBF grant 01KN1105). We thank Sophie Callies for providing us with the pharmacokinetic raw data.

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Muenster, Hittorfstraße 58-62, 48149, Muenster, Germany

    Nina E. Kontny & Georg Hempel

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

    Gudrun Würthwein & Miriam Krischke

  3. Department of Paediatric Haematology and Oncology, University Children’s Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany

    Boos Joachim & Miriam Krischke

  4. Northern Institute for Cancer Research, Newcastle University, Paul O’Gorman Building, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK

    Alan V. Boddy

  5. Department of Pharmacology, University Hospital, University of Cologne, Gleueler Straße 24, 50931, Cologne, Germany

    Uwe Fuhr

  6. Texas Children’s Cancer Center, 6621 Fannin St., MC3-3320, Houston, TX, 77030, USA

    Patrick A. Thompson

  7. Department of Oncology and Hematology, Cantonal Hospital, Rorschacherstraße 95, 9007, St. Gallen, Switzerland

    Markus Jörger

  8. Department of Clinical Pharmacology, Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands

    Jan H. M. Schellens

  9. Department of Pharmaceutical Sciences, Science Faculty, Utrecht University, Utrecht, The Netherlands

    Jan H. M. Schellens

Authors
  1. Nina E. Kontny
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  2. Gudrun Würthwein
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  7. Patrick A. Thompson
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  9. Jan H. M. Schellens
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  10. Georg Hempel
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Corresponding author

Correspondence to Georg Hempel.

Appendix 1: Control stream for the final model

Appendix 1: Control stream for the final model

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Kontny, N.E., Würthwein, G., Joachim, B. et al. Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years. Cancer Chemother Pharmacol 71, 749–763 (2013). https://doi.org/10.1007/s00280-013-2069-1

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  • DOI: https://doi.org/10.1007/s00280-013-2069-1

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