title: Ontogeny and sorafenib metabolism.
abstract: OBJECTIVE
  To investigate the role of ontogeny in sorafenib metabolism to the equipotent active metabolite sorafenib N-oxide.
  
  
  METHODS
  Steady-state pharmacokinetic studies of sorafenib and metabolites were conducted in 30 children and young adults (17 males; median age, 9.5 years) receiving sorafenib 150 mg/m(2) or 200 mg/m(2) twice daily. Sorafenib metabolism was evaluated in vitro at 10 μmol/L using a panel of purified human cytochrome P450 (CYP) enzymes. Sorafenib metabolism and CYP3A4 expression was evaluated in 52 human liver samples from donors of ≤20 years old. The drug-drug interaction potential between sorafenib and azole antifungal agents was evaluated in vitro and in vivo.
  
  
  RESULTS
  No age-related differences in sorafenib apparent oral clearance were observed. Mean sorafenib N-oxide metabolite ratio was 0.27 ± 0.14. In children of ≤10 years of age, boys had approximately 2-fold higher N-oxide ratios than girls (0.40 ± 0.15 vs. 0.22 ± 0.12, P = 0.026). Of the CYPs evaluated, sorafenib was exclusively metabolized to sorafenib N-oxide by CYP3A4. A trend for increased N-oxide formation in boys was observed in liver samples, which correlated with CYP3A4 mRNA expression. Posaconazole and voriconazole potently inhibited sorafenib N-oxide formation in vitro, and reduced sorafenib N-oxide formation in 3 children given sorafenib concurrent with azoles.
  
  
  CONCLUSIONS
  We have identified several factors affecting interpatient variability in sorafenib metabolism to the active N-oxide metabolite including age, sex, and concurrent treatment with azole antifungals. This knowledge may provide important considerations for the clinical use of sorafenib in children and possibly other kinase inhibitors undergoing CYP3A4-mediated metabolism.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Eric I
authors.initials: EI
authors.lastname: Zimmerman
authors.forename: Justin L
authors.initials: JL
authors.lastname: Roberts
authors.forename: Lie
authors.initials: L
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.forename: Alice
authors.initials: A
authors.lastname: Gibson
authors.forename: Amarjit S
authors.initials: AS
authors.lastname: Chaudhry
authors.forename: Erin G
authors.initials: EG
authors.lastname: Schuetz
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Rubnitz
authors.forename: Hiroto
authors.initials: H
authors.lastname: Inaba
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
mesh_terms: D000293:Adolescent; D000367:Age Factors; D001393:Azoles / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008297:Male; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000494:pharmacology; D012737:Sex Factors; D000077157:Sorafenib; D014230:Triazoles / Q000494:pharmacology; D065819:Voriconazole; D055815:Young Adult
chemical_list: D001393:Azoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D009536:Niacinamide; D000077157:Sorafenib; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D065819:Voriconazole