Age-Dependent Pharmacokinetics of Doxorubicin in Children with Cancer
Swantje Völler1, Joachim Boos2, Miriam Krischke3
1Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Muenster, Corrensstraße 48, 48149, Muenster, Germany. s_voel05@uni-muenster.de.
Insights
Doxorubicin clearance is lower in children under three years old. This age-dependent pharmacokinetic difference in doxorubicin is crucial for pediatric dosing, particularly concerning cardiotoxicity.
Area of Science:
- Pharmacology
- Pediatric Oncology
- Pharmacokinetics
Background:
- Limited knowledge exists on doxorubicin pharmacokinetics in children.
- Conflicting evidence suggests potential age-dependent variations.
Purpose of the Study:
- To assess age dependency in doxorubicin clearance (CL) using population pharmacokinetics.
- To develop a pharmacokinetic model for doxorubicin in pediatric patients.
Main Methods:
- Population pharmacokinetic modeling using NONMEM(®) 7.2.0.
- Analysis of data from 94 children (aged 0-18 years) in the EPOC-MS-001-Doxo trial.
- Development of a three-compartment model for doxorubicin and its metabolite doxorubicinol.
Main Results:
- A linear three-compartment model with BSA scaling best described the data.
- Age was identified as a significant covariate, with lower CL in children <3 years (21.1 L/h/m²) compared to older children (26.6 L/h/m²).
- Genetic variations in metabolism/transport enzymes did not influence pharmacokinetics.
Conclusions:
- This is the first model detailing doxorubicin pharmacokinetics in young children (<3 years).
- Lower clearance in younger children necessitates careful dose selection, considering pharmacodynamics and cardiotoxicity.
- Findings are vital for optimizing future pediatric doxorubicin treatment protocols.
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/m(2) in children aged >3 years and 21.1 L/h/m(2) 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.
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