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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

Abstract

Purpose

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/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.

Results

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.

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.

Keywords

Aprepitant Cyclophosphamide Pharmacokinetics Pharmacogenomics 

Notes

Acknowledgments

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).

References

  1. 1.
    Kris MG, Hesketh PJ, Somerfield MR et al (2006) American Society of clinical oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 24:2932–2947PubMedCrossRefGoogle Scholar
  2. 2.
    Warr DG, Hesketh PJ, Gralla RJ, Muss HB, Herrstedt J, Eisenberg PD et al (2005) Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 23:2822–2830PubMedCrossRefGoogle Scholar
  3. 3.
    Aprepitant product information. Merck and Company, Inc., Whitehouse Station; May 2003Google Scholar
  4. 4.
    Majumdar AK, McCrea JB, Panebianco DL, Hesney M, Dru J, Constanzer M et al (2003) Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe. Clin Pharmacol Ther 74:150–156PubMedCrossRefGoogle Scholar
  5. 5.
    McCrea JB, Majumdar AK, Goldberg MR, Iwamoto M, Gargano C, Panebianco DL et al (2003) Effects of the neurokinin 1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther 74:17–24PubMedCrossRefGoogle Scholar
  6. 6.
    Cyclophosphamide product information. Bristol-Myers Squibb Company, Princeton, Nov 2003Google Scholar
  7. 7.
    Chang TKH, Weber GF, Crespi CL, Waxman DJ (1993) Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes. Cancer Res 53:5629–5637PubMedGoogle Scholar
  8. 8.
    Roy P, Yu LJ, Crespi CL, Waxman DJ (1999) Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos 27:655–666PubMedGoogle Scholar
  9. 9.
    Huang Z, Roy P, Waxman DJ (2000) Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochem Pharmacol 59:961–972PubMedCrossRefGoogle Scholar
  10. 10.
    Code EL, Crespi CL, Penman BW, Gonzalez FJ, Chang TKH, Waxman DJ (1997) Human cytochrome P450 2B6: interindividual hepatic expression, substrate specificity, and role in procarcinogen activation. Drug Metab Dispos 25:985–993PubMedGoogle Scholar
  11. 11.
    Hesse LM, Venkatarkrishnan K, Court MH, Von Moltke LL, Duan SX, Shader RI et al (2000) CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos 28:1176–1183PubMedGoogle Scholar
  12. 12.
    Gervot L, Rochat B, Gautier JC, Bohnenstengel F, Kroemer H, de Berardinis V et al (1999) Human CYP2B6: expression, inducibility, and catalytic activities. Pharmacogenetics 9:295–306PubMedCrossRefGoogle Scholar
  13. 13.
    Thummel KE, Wilkinson GR (1998) In vitro and in vivo drug interaction involving human CYP3A. Annu Rev Pharmacol Toxicol 38:389–430PubMedCrossRefGoogle Scholar
  14. 14.
    de Jonge ME, Huitema AD, Holtkamp MJ et al (2005) Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism. Cancer Chemother Pharmacol 56:370–378PubMedCrossRefGoogle Scholar
  15. 15.
    Bubalo JS, Cherala G, McCune JS et al (2011) Aprepitant pharmacokinetics and assessing the impact of aprepitant on cyclophosphamide metabolism in cancer patients undergoing hematopoietic stem cell transplantation. J Clin Pharmacol, published online Mar 15, 2011Google Scholar
  16. 16.
    Sadagopan N, Cohen L, Roberts B et al (2001) Liquid chromatography-tandem mass spectrometric quantitation of cyclophosphamide and its hydroxy metabolite in plasma and tissue for determination of tissue distribution. Chromatogr B Biomed Sci Appl 759:277–284CrossRefGoogle Scholar
  17. 17.
    Anderson LW, Ludeman SM, Colvin OM et al (1995) Quantitation of 4-hydroxycyclophosphamide/aldophosphamide in whole blood. J Chromatogr B Biomed Appl 667:247–257PubMedCrossRefGoogle Scholar
  18. 18.
    Garsa AA, McLeod HL, Marsh S (2005) CYP3A4 and CYP3A5 genotyping by pyrosequencing. BMC Med Genet 6:19. doi: 10.1186/1471-2350-6-19 PubMedCrossRefGoogle Scholar
  19. 19.
    Rohrbacher M, Kirchhof A, Geisslinger G, Lotsch J (2006) Pyrosequencing-based screening for genetic polymorphisms in cytochrome P450 2B6 of potential clinical relevance. Pharmacogenomics 7:995–1002PubMedCrossRefGoogle Scholar
  20. 20.
    Marsh S, King CR, Garsa AA et al (2005) Pyrosequencing of clinically relevant polymorphisms. Methods Mol Biol 311:97–114PubMedGoogle Scholar
  21. 21.
    Batey MA, Wright JG, Azzabi A, Newell DR, Lind MJ, Calvert AH et al (2002) Population pharmacokinetics of adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Eur J Cancer 38:1081–1089PubMedCrossRefGoogle Scholar
  22. 22.
    Jason J, Liao Z (2007) A new approach for outliers in a bioavailability/bioequivalence study. J Biopharm Stat 17:393–405CrossRefGoogle Scholar
  23. 23.
    Boddy AV, Yule SM (2000) Metabolism and pharmacokinetics of oxazaphosphorines. Clin Pharmacokinet 38:291–304PubMedCrossRefGoogle Scholar
  24. 24.
    Struck RF, Alberts DS, Horne K et al (1987) Plasma pharmacokinetics of cyclophosphamide and its cytotoxic metabolites after intravenous versus oral administration in a randomized, crossover trial. Cancer Res 47:2723–2726PubMedGoogle Scholar
  25. 25.
    Lindholm A, Welsh M, Alton C et al (1992) Demographic factors influencing cyclosporine pharmacokinetic parameters in patients with uremia: racial differences in bioavailability. Clin Pharmacol Ther 52:359–371PubMedCrossRefGoogle Scholar
  26. 26.
    Lang CC, Kinirons MT, Robin DR et al (1996) Evidence of increased CYP3A4 activity in African Americans. Clin Pharm Ther 59:158 (abstract 01-B1)Google Scholar
  27. 27.
    Tornuture KM, Biocevich DM, Reed K et al (1995) Methylprednisolone pharmacokinetics, cortisol response and adverse effects in black and white renal transplant recipients. Transplantation 59:729–736CrossRefGoogle Scholar
  28. 28.
    Spatzenegger M, Jaeger W (1995) Clinical importance of hepatic cytochrome P450 in drug metabolism. Drug Metab Rev 27:397–417PubMedCrossRefGoogle Scholar
  29. 29.
    Han HS, Reis I, Kuroi K et al (2009) Racial differences in acute toxicities of adjuvant chemotherapy in patients with breast cancer. J Clin Oncol 27(suppl; abstract e11515)Google Scholar
  30. 30.
    Lawrence HJ, Simone J, Aur RJ (1975) Cyclophosphamide-induced hemorrhagic cystitis in children with leukemia. Cancer 36:1572–1576PubMedCrossRefGoogle Scholar

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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