title: Pharmacokinetic and pharmacodynamic study of doxorubicin in children with cancer: results of a "European Pediatric Oncology Off-patents Medicines Consortium" trial.
abstract: OBJECTIVE
  Doxorubicin is a key component in many pediatric oncology treatment regimens; still pharmacology data on which current dosing regimens are based are very limited.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Age 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.
  
  
  CONCLUSIONS
  In 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.
authors: Pediatric Hematology and Oncology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149, Münster, Germany.|Zentrum für Klinische Studien (ZKS), University Hospital Münster, Von-Esmarch-Straße 62, 48149, Münster, Germany.
authors: Miriam
authors: M
authors: Krischke
authors: Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, 48149, Münster, Germany.
authors: Georg
authors: G
authors: Hempel
authors: Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, 48149, Münster, Germany.
authors: Swantje
authors: S
authors: Völler
authors: INSERM UMR 911, Centre de Recherche en Oncologie biologique et en Oncopharmacologie, Aix-Marseille University, Marseille, France.|Hematology and Pediatric Oncology Department, La Timone University Hospital of Marseille, Marseille, France.
authors: Nicolas
authors: N
authors: André
authors: Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa, 19, 20156, Milan, Italy.
authors: Maurizio
authors: M
authors: D'Incalci
authors: Dipartimento di Pediatria, Clinica di Oncoematologia, via Giustiniani, 3, 35100, Padua, Italy.
authors: Gianni
authors: G
authors: Bisogno
authors: Institute of Biostatistics and Clinical Research, Westfälische Wilhelms-Universität Münster, Schmeddingstraße 56, 48149, Münster, Germany.
authors: Wolfgang
authors: W
authors: Köpcke
authors: Institute of Biostatistics and Clinical Research, Westfälische Wilhelms-Universität Münster, Schmeddingstraße 56, 48149, Münster, Germany.
authors: Matthias
authors: M
authors: Borowski
authors: European Medicines Agency (EMA), 30 Churchill Place, Canary Wharf, London, E14 5EU, UK.
authors: Ralf
authors: R
authors: Herold
authors: Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.|Faculty of Pharmacy, University of Sydney, Sydney, Australia.
authors: Alan V
authors: AV
authors: Boddy
authors: Pediatric Hematology and Oncology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149, Münster, Germany. boosj@uni-muenster.de.
authors: Joachim
authors: J
authors: Boos
mesh_terms: D000293:Adolescent; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D004317:Doxorubicin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D007223:Infant; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D011110:Polymorphism, Genetic; D014336:Troponin / Q000097:blood
chemical_list: D000903:Antibiotics, Antineoplastic; D014336:Troponin; D004317:Doxorubicin
keywords: Cancer; Cardiotoxicity; Children; Doxorubicin; Pharmacokinetic