title: Pharmacokinetics and pharmacogenomics of daunorubicin in children: a report from the Children's Oncology Group.
abstract: OBJECTIVE
  We explored the impact of obesity, body composition, and genetic polymorphisms on the pharmacokinetics (PK) of daunorubicin in children with cancer.
  
  
  METHODS
  Patients ≤21 years receiving daunorubicin as an infusion of any duration <24 h for any type of cancer were eligible. Plasma drug concentrations were measured by high-performance liquid chromatography. Body composition was measured by dual-energy X-ray absorptiometry. Obesity was defined as a BMI >95% for age or as body fat >30%. NONMEM was used to perform PK model fitting. The Affymetrix DMET chip was used for genotyping. The impact of genetic polymorphisms was investigated using SNP/haplotype association analysis with estimated individual PK parameters.
  
  
  RESULTS
  A total of 107 subjects were enrolled, 98 patients had PK sampling, and 50 patients underwent DNA analysis. Population estimates for daunorubicin clearance and volume of distribution were 116 L/m(2)/h ± 14% and 68.1 L/m(2) ± 24%, respectively. Apparent daunorubicinol clearance and volume of distribution were 26.8 L/m(2)/h ± 5.6% and 232 L/m(2) ± 10%, respectively. No effect of body composition or obesity was observed on PK. Forty-four genes with variant haplotypes were tested for association with PK. FMO3-H1/H3 genotype was associated with lower daunorubicin clearance than FMO3-H1/H1, p = 0.00829. GSTP1*B/*B genotype was also associated with lower daunorubicin clearance compared to GSTP1*A/*A, p = 0.0347. However, neither of these associations was significant after adjusting for multiple testing by either Bonferroni or false discovery rate correction.
  
  
  CONCLUSIONS
  We did not detect an effect of body composition or obesity on daunorubicin PK. We found suggestive associations between FMO3 and GSTP1 haplotypes with daunorubicin PK that could potentially affect efficacy and toxicity.
authors.affiliation: Texas Children's Cancer Center, Baylor College of Medicine, 1102 Bates Ave., Suite 1570, Houston, TX, 77030, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Thompson
authors.forename: Heather E
authors.initials: HE
authors.lastname: Wheeler
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Delaney
authors.forename: Rachel
authors.initials: R
authors.lastname: Lorier
authors.forename: Ulrich
authors.initials: U
authors.lastname: Broeckel
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Reaman
authors.forename: Kathleen
authors.initials: K
authors.lastname: Scorsone
authors.forename: Lillian
authors.initials: L
authors.lastname: Sung
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Berg
mesh_terms: D015502:Absorptiometry, Photon; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D001823:Body Composition; D015992:Body Mass Index; D002648:Child; D003630:Daunorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004354:Drug Screening Assays, Antitumor; D005260:Female; D055106:Genome-Wide Association Study; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D015233:Models, Statistical; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D009765:Obesity / Q000150:complications / Q000175:diagnosis; D010105:Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic
chemical_list: D000903:Antibiotics, Antineoplastic; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; C000847:daunorubicinol; D003630:Daunorubicin