Pharmacokinetic and pharmacodynamic study of doxorubicin in children with cancer: results of a “European Pediatric Oncology Off-patents Medicines Consortium” trial

Abstract

PurposeDoxorubicin is a key component in many pediatric oncology treatment regimens; still pharmacology data on which current dosing regimens are based are very limited.MethodsWe conducted a multinational pharmacokinetic study investigating age dependency of doxorubicin metabolism and elimination in children with cancer. One hundred and one patients treated with doxorubicin according to a cancer-specific national or European therapeutic trial were recruited. Doses of doxorubicin ranged from 10.4 to 57.7 mg/m2. Blood samples for measurement of doxorubicin and its metabolite doxorubicinol were collected after two administrations, with five samples collected in children <3 years and eight in children ≥3 years. A population pharmacokinetic approach was used for analysis, including pharmacogenetic covariates. Natriuretic peptides and cardiac troponins were measured to evaluate their role as early indicators of cardiotoxicity.ResultsAge dependence of doxorubicin clearance was demonstrated, with children less than 3 years having a statistically significant lower clearance (21.1 ± 5.8 l/h/m2) than older children (26.6 ± 6.7 l/h/m2) (p = 0.0004) after correcting for body surface area. No effect of the investigated genetic polymorphisms on the pharmacokinetics could be observed. Although natriuretic peptides were transiently elevated after each doxorubicin administration and troponin levels increased with increasing doxorubicin exposure, only limited correlation could be observed between their blood levels and doxorubicin pharmacokinetics.ConclusionIn the European framework of funding and regulatory support, an add-on study to existing therapeutic trials was developed. The pediatric need concerning missing PK data could be addressed with limited burden for the patients. Empirically used dose adaptations for infants were generally found to be justified based on our PK analyses.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-016-3174-8) contains supplementary material, which is available to authorized users.

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

“…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].…”

Pharmacokinetics and population pharmacokinetics in pediatric oncology

“…Krischke et al. showed in a PopPK model that children <3 years of age had a significantly lower clearance compared with older children even after correction for BSA, resulting in higher exposure in younger children . Additionally, Thompson et al.…”

“…showed that doxorubicinol, an active metabolite of doxorubicin, was dependent on body composition: children with >30% body fat showed a significantly lower clearance of doxorubicinol, with a mean of 37 L/h/m² compared with 64 L/h/m² for <30% body fat; however, the groups were small. The metabolite doxorubicinol may contribute to the cardiotoxicity after doxorubicin administration …”

“…With higher dosages, relatively higher concentrations of free prednisolone will be present and could potentially increase the risk of negative side effects. 46 49 Additionally, Thompson et al showed that doxorubicinol, an active metabolite of doxorubicin, was dependent on body composition: children with >30% body fat showed a significantly lower clearance of doxorubicinol, with a mean of 37 L/h/m 2 compared with 64 L/h/m 2 for <30% body fat; however, the groups were small. The metabolite doxorubicinol may contribute to the cardiotoxicity after doxorubicin administration.…”

“…The metabolite doxorubicinol may contribute to the cardiotoxicity after doxorubicin administration. [49][50][51][52]…”