Age-Dependent Pharmacokinetics of Doxorubicin in Children with Cancer.
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.
Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Muenster, Corrensstraße 48, 48149, Muenster, Germany. s_voel05@uni-muenster.de.
Swantje
S
Völler
University Hospital Muenster, Paediatric Haematology and Oncology, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany. boosj@uni-muenster.de.
Joachim
J
Boos
University Hospital Muenster, Centre for Clinical Trials, ZKS Muenster (BMBF 01KN1105), Von-Esmarch-Straße 62, 48149, Muenster, Germany. miriam.krischke@ukmuenster.de.
Miriam
M
Krischke
University Hospital Muenster, Centre for Clinical Trials, ZKS Muenster (BMBF 01KN1105), Von-Esmarch-Straße 62, 48149, Muenster, Germany. wuerthg@ukmuenster.de.
Gudrun
G
Würthwein
Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Muenster, Corrensstraße 48, 48149, Muenster, Germany. nina.kontny@ukmuenster.de.
Nina E
NE
Kontny
Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. alan.boddy@sydney.edu.au.|Faculty of Pharmacy, University of Sydney, Sydney, NSW, 2006, Australia. alan.boddy@sydney.edu.au.
Alan V
AV
Boddy
Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Muenster, Corrensstraße 48, 48149, Muenster, Germany. hempege@uni-muenster.de.
Georg
G
Hempel
D000293:Adolescent; D000367:Age Factors; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007223:Infant; D016014:Linear Models; D008297:Male; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; C010013:adriamycinol