Kuhan Kunarajah1, Stefanie Hennig2, Ross L G Norris2,3,4,5, Michael Lobb3, Bruce G Charles2, Ross Pinkerton6, Andrew S Moore7,8,9. 1. The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia. 2. School of Pharmacy, Pharmacy Australia Centre of Excellence (PACE), The University of Queensland, Brisbane, Australia. 3. Mater Medical Research Institute, The University of Queensland, Brisbane, Australia. 4. School of Pharmacy, Griffith University, Gold Coast, Australia. 5. Department of Clinical Pharmacology, St. Vincent's Hospital, Sydney, NSW, Australia. 6. Oncology Services Group, Children's Health Queensland Hospital and Health Service, Brisbane, Australia. 7. The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia. andrew.moore@uq.edu.au. 8. Oncology Services Group, Children's Health Queensland Hospital and Health Service, Brisbane, Australia. andrew.moore@uq.edu.au. 9. UQ Child Health Research Centre, The University of Queensland, Brisbane, Australia. andrew.moore@uq.edu.au.
Abstract
PURPOSE: Anthracyclines are a mainstay of the treatment of several childhood malignancies, but their utility is limited by dose-related cardiotoxicity. This study is aimed to explore the link between exposure of paediatric cancer patients to doxorubicin and its metabolite doxorubicinol, and cardiac troponin I (cTnI). METHODS: In a prospective pilot study plasma doxorubicin, doxorubicinol, and cTnI concentrations were measured in samples from children undergoing cancer chemotherapy. A mixed-effects population pharmacokinetic model for doxorubicin and doxorubicinol and in combination with a turn-over model for cTnI were developed. RESULTS: Seventeen patients, aged 3.4-14.7 year, treated for a variety of cancers had 99 doxorubicin and 119 doxorubicinol concentrations analysed from samples drawn between 0.5 and 336 h after the start of the infusion. Eleven patients had received previous doses of anthracyclines, with a median cumulative prior dose of 90 mg/m2 (range 0-225 mg/m2). The median administered doxorubicin dose was 30 mg/m2 (range 25-75 mg/m2). Doxorubicin disposition was described by a three-compartment model with first-order elimination and metabolism to doxorubicinol. Body surface area was related to all clearance and distribution parameters and age further influenced clearance (CL, 58.7 L/h/1.8 m2 for an average 8.4-year-old patient). Combined doxorubicin and metabolite exposure stimulated a temporary increase in cTnI in plasma, with a concentration of 11.8 µg/L required to achieve half-maximal effect. Prior cumulative anthracycline dosage received by patients was predictive of an increased cTnI baseline prior to a new doxorubicin dose. CONCLUSION: Prior anthracycline exposure increased baseline cTnI in a dose-dependent manner, consistent with the known cumulative risk of anthracycline exposure-induced cardiotoxicity.
PURPOSE:Anthracyclines are a mainstay of the treatment of several childhood malignancies, but their utility is limited by dose-related cardiotoxicity. This study is aimed to explore the link between exposure of paediatric cancerpatients to doxorubicin and its metabolite doxorubicinol, and cardiac troponin I (cTnI). METHODS: In a prospective pilot study plasma doxorubicin, doxorubicinol, and cTnI concentrations were measured in samples from children undergoing cancer chemotherapy. A mixed-effects population pharmacokinetic model for doxorubicin and doxorubicinol and in combination with a turn-over model for cTnI were developed. RESULTS: Seventeen patients, aged 3.4-14.7 year, treated for a variety of cancers had 99 doxorubicin and 119 doxorubicinol concentrations analysed from samples drawn between 0.5 and 336 h after the start of the infusion. Eleven patients had received previous doses of anthracyclines, with a median cumulative prior dose of 90 mg/m2 (range 0-225 mg/m2). The median administered doxorubicin dose was 30 mg/m2 (range 25-75 mg/m2). Doxorubicin disposition was described by a three-compartment model with first-order elimination and metabolism to doxorubicinol. Body surface area was related to all clearance and distribution parameters and age further influenced clearance (CL, 58.7 L/h/1.8 m2 for an average 8.4-year-old patient). Combined doxorubicin and metabolite exposure stimulated a temporary increase in cTnI in plasma, with a concentration of 11.8 µg/L required to achieve half-maximal effect. Prior cumulative anthracycline dosage received by patients was predictive of an increased cTnI baseline prior to a new doxorubicin dose. CONCLUSION: Prior anthracycline exposure increased baseline cTnI in a dose-dependent manner, consistent with the known cumulative risk of anthracycline exposure-induced cardiotoxicity.
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