A pilot study to investigate the relationship between doxorubicin and doxorubicinol pharmacokinetics and cardiotoxicity in children and adolescents with cancer

Aims: The primary aim of this pilot study was to assess the relationship between doxorubicin (dox) and doxorubicinol (doxinol) pharmacokinetics (PK) and markers of cardiotoxicity (cardiac troponin I (cTnI)), determine PK variability and identify covariates explaining the variability in the PK in children and adolescents with cancer.

Methods: A prospective pilot study measured plasma dox and doxinol and cardiac troponin I (cTnI) in children undergoing chemotherapy treatment at the Royal Children's Hospital, now Lady Cilento Children's Hospital, Brisbane, Australia. A population parent-metabolite pharmacokinetic (PK) model for dox and doxinol as well as a turnover-model for cTnI were developed using a non-linear mixed effects modelling approach (NONMEM v7.3). A population PK model of dox and doxinol was developed first, guided by previous models in the literature (1, 2), whose exposure was then stimulating the release of cTnI into the blood. Between subject variability (BSV) and between occasion variability (BOV) were estimated. A covariate analysis to identify influential factors explaining variability was performed.

Results: 17 children (6 female) aged 3.4 – 14.7 years (median 7.0) being treated for a variety of cancers had blood sampled after 1 or 2 two doses of dox (total of 24 doses of dox). Eleven patients had received doses of anthracyclines prior to the fist observed dose in this study, six patients didn't (median cumulative prior dose 90 mg/m2, range 0-225 mg/m2). The median dox dose administered was 30 mg/m2 (range 25-75 mg/m2) given over 1 h (range 0.25 – 72.5 h). First samples were taken from 0.5 to 336 h after the start of the infusion. Measured dox concentrations (n=100) ranged from 0.01 – 39.4 mcg/L, doxinol concentrations (n=120) ranged from 0.01 – 57.7 mcg/L, and cTnI (n=104) ranged from 0.05 – 0.1 ng/mL. The best fit of the model to the data shown in Figure 1. Dox clearance from the central compartment was estimated as 58.9 L/h/1.8 m2 for an average 8.4-yearold (BSV= 19.8%, BOV=9%), central volume of distribution was 33.4 L/1.8 m2. Doxinol clearance was 18.1 L/h/1.8 m2 (BSV= 28.8%), and volume of distribution was 454 L/1.8 m2. Body surface area (BSV) was added as a covariate on all clearance and distribution parameters for dox and doxinol, as well as age on dox clearance. Dox and doxinol exposure stimulated the release of cTnI into the blood, which was modelled via an Emax function(3). Emax = 0.557, Kdeg = 0.18 h-1 (t1/2=3.8), EC50=9.1 microg/L, Baseline = 15 pg/mL (fixed, BSV= 7.5%, BOV= 45%). The baseline increased by 0.1% with every 1 mg/m2 increase in prior cumulative anthracyclines doses.   

Figure 1: Final model (dox =black, doxinol = red, cTnI = blue, significant covariates = purple)

Conclusion: The PK of dox and doxinol was described satisfactorily, and parameter estimates were comparable to those previously reported in similar patients (1, 2). This pilot study further found that prior anthracycline exposure increased the risk of anthracycline exposure-induced cardiotoxicity; however this effect should be evaluated further. The study contributes to an improved understanding the dose-concentration-toxicity relationship in children with cancer.

 References:

1.                     Kontny NE, Wurthwein G, Joachim B, Boddy AV, Krischke M, Fuhr U, et al. Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years. Cancer Chemother Pharmacol. 2013;71(3):749-63.

2.                     Voller S, Boos J, Krischke M, Wurthwein G, Kontny NE, Boddy AV, et al. Age-Dependent Pharmacokinetics of Doxorubicin in Children with Cancer. Clin Pharmacokinet. 2015;54(11):1139-49.

3.                     Mikaelian I, Dunn ME, Mould DR, Hirkaler G, Geng W, Coluccio D, et al. Differential analysis of transient increases of serum cTnI in response to handling in rats. Pharmacol Res Perspect. 2013;1(2):e00011.