Age-Dependent Pharmacokinetics of Doxorubicin in Children with Cancer
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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.
KeywordsDoxorubicin Body Surface Area Population Pharmacokinetic Analysis Objective Function Value Carbonyl Reductase
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.
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