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dc.contributor.authorKunarajah, Kuhan
dc.contributor.authorHennig, Stefanie
dc.contributor.authorNorris, Ross
dc.contributor.authorLobb, Michael
dc.contributor.authorCharles, Bruce G.
dc.contributor.authorPinkerton, Ross
dc.contributor.authorMoore, Andrew S.
dc.description.abstractPurpose: 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.
dc.relation.ispartofjournalCancer Chemotherapy and Pharmacology
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences not elsewhere classified
dc.titlePopulation pharmacokinetic modelling of doxorubicin and doxorubicinol in children with cancer: is there a relationship with cardiac troponin profiles?
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorNorris, Ross LG.

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