Population pharmacokinetic modelling of doxorubicin and doxorubicinol in children with cancer: is there a relationship with cardiac troponin profiles?

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.