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

Kunarajah, Kuhan, Hennig S., Norris, Ross L. G., Lobb, Michael, Charles, Bruce G., Pinkerton, Ross and Moore, Andrew S. (2017) Population pharmacokinetic modelling of doxorubicin and doxorubicinol in children with cancer: is there a relationship with cardiac troponin profiles?. Cancer Chemotherapy and Pharmacology, 80 1: 15-25. doi:10.1007/s00280-017-3309-6


Author Kunarajah, Kuhan
Hennig S.
Norris, Ross L. G.
Lobb, Michael
Charles, Bruce G.
Pinkerton, Ross
Moore, Andrew S.
Title Population pharmacokinetic modelling of doxorubicin and doxorubicinol in children with cancer: is there a relationship with cardiac troponin profiles?
Journal name Cancer Chemotherapy and Pharmacology   Check publisher's open access policy
ISSN 1432-0843
0344-5704
Publication date 2017-04-25
Year available 2017
Sub-type Article (original research)
DOI 10.1007/s00280-017-3309-6
Open Access Status File (Author Post-print)
Volume 80
Issue 1
Start page 15
End page 25
Total pages 11
Place of publication Heidelberg, Germany
Publisher Springer Verlag
Language eng
Subject 2730 Oncology
3005 Toxicology
3004 Pharmacology
1306 Cancer Research
2736 Pharmacology (medical)
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/m (range 0–225 mg/m). The median administered doxorubicin dose was 30 mg/m (range 25–75 mg/m). 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 m 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.
Formatted 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.
Keyword Doxorubicin
Anthracycline
Pharmacokinetics
Cardiotoxicity
Troponin
Children
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 3 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 2 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 23 May 2017, 00:05:21 EST by Web Cron on behalf of School of Pharmacy