Pharmacokinetics and pharmacogenomics of daunorubicin in children: a report from the Children's Oncology Group. Cancer Chemother Pharmacol 2014 Oct;74(4):831-8
Date
08/15/2014Pubmed ID
25119182Pubmed Central ID
PMC4282931DOI
10.1007/s00280-014-2535-4Scopus ID
2-s2.0-84939890862 (requires institutional sign-in at Scopus site) 20 CitationsAbstract
PURPOSE: We explored the impact of obesity, body composition, and genetic polymorphisms on the pharmacokinetics (PK) of daunorubicin in children with cancer.
PATIENTS AND 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.
Author List
Thompson P, Wheeler HE, Delaney SM, Lorier R, Broeckel U, Devidas M, Reaman GH, Scorsone K, Sung L, Dolan ME, Berg SLAuthor
Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Absorptiometry, PhotonAntibiotics, Antineoplastic
Body Composition
Body Mass Index
Child
Daunorubicin
Drug Screening Assays, Antitumor
Female
Genome-Wide Association Study
Glutathione S-Transferase pi
Haplotypes
Humans
Male
Metabolic Clearance Rate
Models, Statistical
Neoplasms
Obesity
Oxygenases
Pharmacogenetics
Polymorphism, Genetic
