Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 5, pp 1189–1196 | Cite as

The effect of aprepitant and race on the pharmacokinetics of cyclophosphamide in breast cancer patients

  • Christine M. WalkoEmail author
  • Austin J. Combest
  • Ivan Spasojevic
  • Angela Y. C. Yu
  • Shriya Bhushan
  • J. Heyward Hull
  • Janelle Hoskins
  • Delma Armstrong
  • Lisa Carey
  • Frances Collicio
  • E. Claire Dees
Original Article



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.


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/m2 and doxorubicin 60 mg/m2. 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.


The geometric mean area under concentration–time curve (AUC0−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 AUC0−t (μg/mL h) was 6.80 following aprepitant and 6.96 following placebo (ratio 0.98; 90% CI 0.88, 1.08). DCE AUC0−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 lnAUC0−t (P = 0.0169) as African Americans had approximately a 2-fold higher DCE AUC than Caucasians.


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.


Aprepitant Cyclophosphamide Pharmacokinetics Pharmacogenomics 



The authors thank Celeste Lindley, Pharm.D. for her support with study design. This study was supported by Merck Pharmaceuticals and by the General Clinical Research Centers Program of Division of Research Resources, National Institutes of Health (RR00046).


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Christine M. Walko
    • 1
    • 4
    Email author
  • Austin J. Combest
    • 1
  • Ivan Spasojevic
    • 6
  • Angela Y. C. Yu
    • 1
  • Shriya Bhushan
    • 1
  • J. Heyward Hull
    • 5
  • Janelle Hoskins
    • 4
  • Delma Armstrong
    • 2
  • Lisa Carey
    • 2
    • 3
  • Frances Collicio
    • 2
    • 3
  • E. Claire Dees
    • 2
    • 3
  1. 1.UNC Eshelman School of PharmacyUniversity of North CarolinaChapel HillUSA
  2. 2.Division of Hematology-Oncology, Department of Medicine, School of MedicineUniversity of North CarolinaChapel HillUSA
  3. 3.Lineberger Comprehensive Cancer CenterChapel HillUSA
  4. 4.Division of Pharmacotherapy and Experimental Therapeutics, Institute of Pharmacogenomics and Individualized Therapy, UNC School of PharmacyUniversity of North CarolinaChapel HillUSA
  5. 5.Division of Pharmacotherapy and Experimental TherapeuticsUNC School of PharmacyChapel HillUSA
  6. 6.Duke Cancer Institute Clinical Pharmacology LaboratoryDuke University Medical CenterDurhamUSA

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