dc.contributor.author | Kunarajah, Kuhan | |
dc.contributor.author | Hennig, Stefanie | |
dc.contributor.author | Norris, Ross | |
dc.contributor.author | Lobb, Michael | |
dc.contributor.author | Charles, Bruce G. | |
dc.contributor.author | Pinkerton, Ross | |
dc.contributor.author | Moore, Andrew S. | |
dc.date.accessioned | 2018-06-19T01:30:21Z | |
dc.date.available | 2018-06-19T01:30:21Z | |
dc.date.issued | 2017 | |
dc.identifier.issn | 0344-5704 | |
dc.identifier.doi | 10.1007/s00280-017-3309-6 | |
dc.identifier.uri | http://hdl.handle.net/10072/344269 | |
dc.description.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. | |
dc.description.peerreviewed | Yes | |
dc.language | English | |
dc.language.iso | eng | |
dc.publisher | Springer | |
dc.relation.ispartofpagefrom | 15 | |
dc.relation.ispartofpageto | 25 | |
dc.relation.ispartofissue | 1 | |
dc.relation.ispartofjournal | Cancer Chemotherapy and Pharmacology | |
dc.relation.ispartofvolume | 80 | |
dc.subject.fieldofresearch | Pharmacology and pharmaceutical sciences | |
dc.subject.fieldofresearch | Pharmacology and pharmaceutical sciences not elsewhere classified | |
dc.subject.fieldofresearchcode | 3214 | |
dc.subject.fieldofresearchcode | 321499 | |
dc.title | Population pharmacokinetic modelling of doxorubicin and doxorubicinol in children with cancer: is there a relationship with cardiac troponin profiles? | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dc.type.code | C - Journal Articles | |
gro.hasfulltext | No Full Text | |
gro.griffith.author | Norris, Ross LG. | |