Swantje Völler1, Joachim Boos2, Miriam Krischke3, Gudrun Würthwein4, Nina E Kontny5, Alan V Boddy6,7, Georg Hempel8. 1. Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Muenster, Corrensstraße 48, 48149, Muenster, Germany. s_voel05@uni-muenster.de. 2. University Hospital Muenster, Paediatric Haematology and Oncology, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany. boosj@uni-muenster.de. 3. University Hospital Muenster, Centre for Clinical Trials, ZKS Muenster (BMBF 01KN1105), Von-Esmarch-Straße 62, 48149, Muenster, Germany. miriam.krischke@ukmuenster.de. 4. University Hospital Muenster, Centre for Clinical Trials, ZKS Muenster (BMBF 01KN1105), Von-Esmarch-Straße 62, 48149, Muenster, Germany. wuerthg@ukmuenster.de. 5. Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Muenster, Corrensstraße 48, 48149, Muenster, Germany. nina.kontny@ukmuenster.de. 6. Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. alan.boddy@sydney.edu.au. 7. Faculty of Pharmacy, University of Sydney, Sydney, NSW, 2006, Australia. alan.boddy@sydney.edu.au. 8. Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Muenster, Corrensstraße 48, 48149, Muenster, Germany. hempege@uni-muenster.de.
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 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.
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.
Authors: Ron J Keizer; Michel van Benten; Jos H Beijnen; Jan H M Schellens; Alwin D R Huitema Journal: Comput Methods Programs Biomed Date: 2010-06-02 Impact factor: 5.428
Authors: Javier G Blanco; Can-Lan Sun; Wendy Landier; Lu Chen; Diego Esparza-Duran; Wendy Leisenring; Allison Mays; Debra L Friedman; Jill P Ginsberg; Melissa M Hudson; Joseph P Neglia; Kevin C Oeffinger; A Kim Ritchey; Doojduen Villaluna; Mary V Relling; Smita Bhatia Journal: J Clin Oncol Date: 2011-11-28 Impact factor: 44.544
Authors: Nina E Kontny; Gudrun Würthwein; Boos Joachim; Alan V Boddy; Miriam Krischke; Uwe Fuhr; Patrick A Thompson; Markus Jörger; Jan H M Schellens; Georg Hempel Journal: Cancer Chemother Pharmacol Date: 2013-01-13 Impact factor: 3.333
Authors: Elly Barry; Jorge A Alvarez; Rebecca E Scully; Tracie L Miller; Steven E Lipshultz Journal: Expert Opin Pharmacother Date: 2007-06 Impact factor: 3.889
Authors: Rachel J Ryu; Sara Eyal; Henry G Kaplan; Arezoo Akbarzadeh; Karen Hays; Kristin Puhl; Thomas R Easterling; Stacey L Berg; Kathleen A Scorsone; Eric M Feldman; Jason G Umans; Menachem Miodovnik; Mary F Hebert Journal: Cancer Chemother Pharmacol Date: 2014-02-15 Impact factor: 3.333
Authors: J Gartrell; J C Panetta; S D Baker; Y L Chen; D S Hawkins; A Ostrenga; T J Scharschmidt; S L Spunt; D Wang; A R Weiss Journal: Cancer Chemother Pharmacol Date: 2022-01-27 Impact factor: 3.333
Authors: Jonás Samuel Pérez-Blanco; Dolores Santos-Buelga; María Del Mar Fernández de Gatta; Jesús María Hernández-Rivas; Alejandro Martín; María José García Journal: Br J Clin Pharmacol Date: 2016-09-06 Impact factor: 4.335
Authors: Miriam Krischke; Georg Hempel; Swantje Völler; Nicolas André; Maurizio D'Incalci; Gianni Bisogno; Wolfgang Köpcke; Matthias Borowski; Ralf Herold; Alan V Boddy; Joachim Boos Journal: Cancer Chemother Pharmacol Date: 2016-10-21 Impact factor: 3.333
Authors: A Laura Nijstad; Shelby Barnett; Arief Lalmohamed; Inez M Bérénos; Elizabeth Parke; Vickyanne Carruthers; Deborah A Tweddle; Jordon Kong; C Michel Zwaan; Alwin D R Huitema; Gareth J Veal Journal: Eur J Cancer Date: 2021-12-02 Impact factor: 9.162
Authors: Christian Siebel; Gudrun Würthwein; Claudia Lanvers-Kaminsky; Nicolas André; Frank Berthold; Ilaria Castelli; Pascal Chastagner; François Doz; Martin English; Gabriele Escherich; Michael C Frühwald; Norbert Graf; Andreas H Groll; Antonio Ruggiero; Georg Hempel; Joachim Boos Journal: BMC Pharmacol Toxicol Date: 2020-05-28 Impact factor: 2.483