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Age-Dependent Pharmacokinetics of Doxorubicin in Children with Cancer

Lookup NU author(s): Professor Alan Boddy

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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 NONMEMA (R) 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/m(2) in children aged > 3 years and 21.1 L/h/m(2) in children aged a parts per thousand currency sign3 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.

Publication metadata

Author(s): Voller S, Boos J, Krischke M, Wurthwein G, Kontny NE, Boddy AV, Hempel G

Publication type: Article

Publication status: Published

Journal: Clinical Pharmacokinetics

Year: 2015

Volume: 54

Issue: 11

Pages: 1139-1149

Print publication date: 01/11/2015

Online publication date: 30/04/2015

ISSN (print): 0312-5963

ISSN (electronic): 1179-1926

Publisher: Adis International Ltd.

URL: http://dx.doi.org/10.1007/s40262-015-0272-4

DOI: 10.1007/s40262-015-0272-4

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