title: The effect of aprepitant and race on the pharmacokinetics of cyclophosphamide in breast cancer patients.
abstract: OBJECTIVE
  The prodrug cyclophosphamide is metabolized by cytochrome P450(CYP)2B6 to the active metabolite, 4-hydroxycyclophosphamide (4-OH), and by CYP3A4/5 to toxic chloracetaldehyde and 2-dechloroethylcyclophosphamide (DCE). Since aprepitant is a moderate inhibitor of CYP3A4, the study was designed to determine whether its concurrent use alters the pharmacokinetics (PK) of cyclophosphamide. In addition, we sought to determine the effect of race and pharmacogenomics on cyclophosphamide PK.
  
  
  METHODS
  Eighteen patients with localized breast cancer were randomized in this double-blinded cross-over study to receive aprepitant or placebo in addition to cyclophosphamide 600 mg/m(2) and doxorubicin 60 mg/m(2). Blood samples were collected for both PK analysis of cyclophosphamide and metabolites and pharmacogenomic analysis. Single nucleotide polymorphisms genotyped were CYP3A4*1B, CYP3A5*3, and CYP2B6*6.
  
  
  RESULTS
  The geometric mean area under concentration-time curve (AUC(0-t) μg/mL h) for cyclophosphamide was 282 following aprepitant and 230 following placebo (ratio 1.23; 90% CI 1.13, 1.33). 4-OH AUC(0-t) (μg/mL h) was 6.80 following aprepitant and 6.96 following placebo (ratio 0.98; 90% CI 0.88, 1.08). DCE AUC(0-t) (μg/mL h) was 6.76 following aprepitant and 9.37 following placebo (ratio 0.72; 90% CI 0.64, 0.81). Genotype analysis was confounded by race. Race was a significant predictor of DCE lnAUC(0-t) (P = 0.0169) as African Americans had approximately a 2-fold higher DCE AUC than Caucasians.
  
  
  CONCLUSIONS
  Aprepitant altered the exposure of cyclophosphamide and DCE but not the active 4-OH metabolite, making it unlikely that aprepitant would change the clinical efficacy of cyclophosphamide. African Americans were also found to have altered PK compared with Caucasian patients.
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7569, USA. cwalko@email.unc.edu
authors.forename: Christine M
authors.initials: CM
authors.lastname: Walko
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Combest
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.forename: Angela Y C
authors.initials: AY
authors.lastname: Yu
authors.forename: Shriya
authors.initials: S
authors.lastname: Bhushan
authors.forename: J Heyward
authors.initials: JH
authors.lastname: Hull
authors.forename: Janelle
authors.initials: J
authors.lastname: Hoskins
authors.forename: Delma
authors.initials: D
authors.lastname: Armstrong
authors.forename: Lisa
authors.initials: L
authors.lastname: Carey
authors.forename: Frances
authors.initials: F
authors.lastname: Collicio
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
mesh_terms: D000328:Adult; D001741:Black or African American / Q000706:statistics & numerical data; D000368:Aged; D000932:Antiemetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077608:Aprepitant; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000188:drug therapy* / Q000473:pathology; D018592:Cross-Over Studies; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004311:Double-Blind Method; D004317:Doxorubicin / Q000008:administration & dosage; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000706:statistics & numerical data
chemical_list: D000932:Antiemetics; D009025:Morpholines; D000077608:Aprepitant; D004317:Doxorubicin; D003520:Cyclophosphamide; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C510164:CYP3A5 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating