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

Kunarajah, Kuhan; Hennig, Stefanie; Norris, Ross; Lobb, Michael; Charles, Bruce G.; Pinkerton, Ross; Moore, Andrew S.

doi:10.1007/s00280-017-3309-6

Cited by 13 publications

(36 citation statements)

References 31 publications

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“…TnI is more feasible than the other cardiac troponins for early CIC diagnosis due to its kinetic curve [18], but the exact dynamic of troponin release into bloodstream is not well known [5,12,19]. Although several papers have been published regarding CIC evaluation by troponin measurements, there are only a few studies on this subject in pediatric ALL setting [20][21][22][23][24][25][26][27][28][29]. Different groups monitored large cohorts of children with ALL and concluded that TnI was predictable for myocardial injury [20][21][22].…”

Section: Discussionmentioning

confidence: 99%

“…Different groups monitored large cohorts of children with ALL and concluded that TnI was predictable for myocardial injury [20][21][22]. There is evidence that TnI level is correlated with AC treatment in a dose-dependent manner [23][24] and the increase occurs 2-4 weeks after administration [25] but there are studies in which no changes in the troponin values during AC treatment were found [26][27][28][29]. In our study, in children with ALL receiving low CD of AC, TnI increased in direct proportion with the number of doses (p<0.001), only one hour after the administration.…”

Section: Discussionmentioning

confidence: 99%

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Cardiotoxicity evaluation in pediatric patients with acute lymphoblastic leukemia – results of prospective study

et al. 2019

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Aim: The chemotherapy protocol for acute lymphoblastic leukemia (ALL) uses low doses of anthracyclines (AC), generally associated with subclinical cardiotoxicity. The aim of our study was to evaluate the serum biomarkers and echocardiography parameters in children with ALL treated with AC in order to determine the most useful element for early detection of cardiotoxicity.Material and methods: In this prospective study, troponin I (TnI) and heart-type fatty acid binding protein (HFABP) were assessed five times during the first year after the onset of ALL. Serial Tissue Doppler Imaging and conventional cardiac echography were performed by two pediatric cardiologists (intraclass correlation coefficient over 0.85 for all measurements) in three periods during the study protocol.Results: We evaluated 48 children with ALL. TnI increased during therapy, without returning to baseline values one year after diagnosis. HFABP did not show significant changes during the study protocol. Left ventricle outflow tract time-velocity integral and peak systolic septal mitral annulus velocity decreased during chemotherapy and returned to baseline levels at one year after diagnosis, while peak systolic tricuspid annulus velocity and excursion, maintained a descending tendency. Early filling transmitral flow velocity and E/A ratio were also transiently influenced by chemotherapy.Conclusions: The study showed signs of transient cardiotoxicity in the left ventricle and diastolic parameters after chemotherapy, compared to right ventricle parameters which maintained low values even one year after diagnosis. TnI proved to be directly proportional to chemotherapy doses but HFABP was not useful in this setting

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cardiotoxicity evaluation in pediatric patients with acute lymphoblastic leukemia – results of prospective study

et al. 2019

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“…In 19 children (3–15 years) who underwent sparse sampling up to 168 hours postinfusion over multiple doxorubicin doses, Kunarajah et al 60 also reported a mean doxorubicin clearance similar to that of adults (58.7 L/h/1.8m 2 ) with a significant effect of BSA scaling and age (as a power function) on doxorubicin clearance, and of BSA scaling on volume of distribution. Doxorubicin clearance in the very young is consistently reported to be significantly lower than in older children, 59,60,67 even when adjusted for BSA, with calculated values for a neonate 60 of 9.1 L/h/m 2 and 12.0 L/h/m 2 67 compared to 29.0 and 24.1 L/h/m 2 in a 5 year old, respectively. Importantly, Voller et al 67 have proposed that whilst BSA adjusts clearance for body size, age further adjusts for the maturation of clearance pathways.…”

Section: Pharmacokinetic Modelsmentioning

confidence: 95%

Is there scope for better individualisation of anthracycline cancer chemotherapy?

Sallustio

Boddy

2020

Brit J Clinical Pharma

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Anthracyclines are used to treat solid and haematological cancers, particularly breast cancers, lymphomas and childhood cancers. Myelosuppression and cardiotoxicity are the primary toxicities that limit treatment duration and/or intensity. Cardiotoxicity, particularly heart failure, is a leading cause of morbidity and mortality in cancer survivors. Cumulative anthracycline dose is a significant predictor of cardiotoxicity risk, suggesting a role for anthracycline pharmacokinetic variability. Population pharmacokinetic modelling in children has shown that doxorubicin clearance in the very young is significantly lower than in older children, potentially contributing to their higher risk of cardiotoxicity. A model of doxorubicin clearance based on body surface area and age offers a patient‐centred dose‐adjustment strategy that may replace the current disparate initial‐dose selection tools, providing a rational way to compensate for pharmacokinetic variability in children aged <7 years. Population pharmacokinetic models in adults have not adequately addressed older ages, obesity, hepatic and renal dysfunction, and potential drug–drug interactions to enable clinical application. Although candidate gene and genome‐wide association studies have investigated relationships between genetic variability and anthracycline pharmacokinetics or clinical outcomes, there have been few clinically significant reproducible associations. Precision‐dosing of anthracyclines is currently hindered by lack of clinically useful pharmacokinetic targets and models that predict cumulative anthracycline exposures. Combined with known risk factors for cardiotoxicity, the use of advanced echocardiography and biomarkers, future validated pharmacokinetic targets and predictive models could facilitate anthracycline precision dosing that truly maximises efficacy and provides individualised early intervention with cardioprotective therapies in patients at risk of cardiotoxicity.

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“…Kunarajah and colleagues used an E max model to link combined plasma concentrations of doxorubicin (DXR) and its primary metabolite, doxorubicinol (DXR-ol), with the cardiac troponin index (cTnI) as a marker of cardiotoxicity in 17 children. 58 They were able to predict DXR and DXR-ol concentrations and cTnI after DXR dosing. They could also calculate the combined concentration of DXR and DXR-ol, which resulted in half-maximal cTnI increase.…”

Section: Clinical Perspectivementioning

confidence: 97%

“…Such equations can be easily rearranged to describe inhibition. Kunarajah and colleagues used an E max model to link combined plasma concentrations of doxorubicin (DXR) and its primary metabolite, doxorubicinol (DXR‐ol), with the cardiac troponin index (cTnI) as a marker of cardiotoxicity in 17 children . They were able to predict DXR and DXR‐ol concentrations and cTnI after DXR dosing.…”

Section: Clinical Perspectivementioning

confidence: 99%

Pharmacometric Modeling and Simulation Is Essential to Pediatric Clinical Pharmacology

Neely

Bayard

Desai

et al. 2018

The Journal of Clinical Pharma

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Pediatric clinical pharmacology now encompasses a wide range of activities, including drug pharmacokinetic and pharmacodynamic modeling and simulation, also known as pharmacometrics. Pediatric clinical pharmacologists may be physicians but are more likely to be pharmacists or PhD scientists, and pediatric clinical pharmacology today is largely a research specialty rather than a subspecialty for direct patient care. Pharmacometrics, including “top‐down” population modeling and “bottom‐up” physiologically based pharmacokinetic modeling, has become an indispensable tool for pharmaceutical industry scientists, government regulators, academic researchers, and even a handful of patient‐oriented practitioners. This review summarizes the application of pharmacometrics within each of these domains and predicts future trends of further applications across the spectrum of pediatric clinical pharmacology from drug development to patient care.

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

Abstract: Prior anthracycline exposure increased baseline cTnI in a dose-dependent manner, consistent with the known cumulative risk of anthracycline exposure-induced cardiotoxicity.

Cited by 13 publications

References 31 publications

Cardiotoxicity evaluation in pediatric patients with acute lymphoblastic leukemia – results of prospective study

Cardiotoxicity evaluation in pediatric patients with acute lymphoblastic leukemia – results of prospective study

Is there scope for better individualisation of anthracycline cancer chemotherapy?

Pharmacometric Modeling and Simulation Is Essential to Pediatric Clinical Pharmacology

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