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

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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.

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References

  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 24:2932–2947

    Article  PubMed  CAS  Google Scholar 

  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 23:2822–2830

    Article  PubMed  CAS  Google Scholar 

  3. Aprepitant product information. Merck and Company, Inc., Whitehouse Station; May 2003

  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 74:150–156

    Article  PubMed  CAS  Google Scholar 

  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 74:17–24

    Article  PubMed  CAS  Google Scholar 

  6. Cyclophosphamide product information. Bristol-Myers Squibb Company, Princeton, Nov 2003

  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 53:5629–5637

    PubMed  CAS  Google Scholar 

  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 27:655–666

    PubMed  CAS  Google Scholar 

  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 59:961–972

    Article  PubMed  CAS  Google Scholar 

  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 25:985–993

    PubMed  CAS  Google Scholar 

  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 28:1176–1183

    PubMed  CAS  Google Scholar 

  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 9:295–306

    Article  PubMed  CAS  Google Scholar 

  13. Thummel KE, Wilkinson GR (1998) In vitro and in vivo drug interaction involving human CYP3A. Annu Rev Pharmacol Toxicol 38:389–430

    Article  PubMed  CAS  Google Scholar 

  14. de Jonge ME, Huitema AD, Holtkamp MJ et al (2005) Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism. Cancer Chemother Pharmacol 56:370–378

    Article  PubMed  Google Scholar 

  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, 2011

  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 759:277–284

    Article  CAS  Google Scholar 

  17. Anderson LW, Ludeman SM, Colvin OM et al (1995) Quantitation of 4-hydroxycyclophosphamide/aldophosphamide in whole blood. J Chromatogr B Biomed Appl 667:247–257

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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 7:995–1002

    Article  PubMed  CAS  Google Scholar 

  20. Marsh S, King CR, Garsa AA et al (2005) Pyrosequencing of clinically relevant polymorphisms. Methods Mol Biol 311:97–114

    PubMed  CAS  Google Scholar 

  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 38:1081–1089

    Article  PubMed  CAS  Google Scholar 

  22. Jason J, Liao Z (2007) A new approach for outliers in a bioavailability/bioequivalence study. J Biopharm Stat 17:393–405

    Article  Google Scholar 

  23. Boddy AV, Yule SM (2000) Metabolism and pharmacokinetics of oxazaphosphorines. Clin Pharmacokinet 38:291–304

    Article  PubMed  CAS  Google Scholar 

  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 47:2723–2726

    PubMed  CAS  Google Scholar 

  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 52:359–371

    Article  PubMed  CAS  Google Scholar 

  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. Tornuture KM, Biocevich DM, Reed K et al (1995) Methylprednisolone pharmacokinetics, cortisol response and adverse effects in black and white renal transplant recipients. Transplantation 59:729–736

    Article  Google Scholar 

  28. Spatzenegger M, Jaeger W (1995) Clinical importance of hepatic cytochrome P450 in drug metabolism. Drug Metab Rev 27:397–417

    Article  PubMed  CAS  Google Scholar 

  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)

  30. Lawrence HJ, Simone J, Aur RJ (1975) Cyclophosphamide-induced hemorrhagic cystitis in children with leukemia. Cancer 36:1572–1576

    Article  PubMed  CAS  Google Scholar 

Download references

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).

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Authors and Affiliations

  1. UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA

    Christine M. Walko, Austin J. Combest, Angela Y. C. Yu & Shriya Bhushan

  2. Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA

    Delma Armstrong, Lisa Carey, Frances Collicio & E. Claire Dees

  3. Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

    Lisa Carey, Frances Collicio & E. Claire Dees

  4. Division of Pharmacotherapy and Experimental Therapeutics, Institute of Pharmacogenomics and Individualized Therapy, UNC School of Pharmacy, University of North Carolina, CB 7569, Chapel Hill, NC, 27599-7569, USA

    Christine M. Walko & Janelle Hoskins

  5. Division of Pharmacotherapy and Experimental Therapeutics, UNC School of Pharmacy, CB 7569, Chapel Hill, NC, 27599-7569, USA

    J. Heyward Hull

  6. Duke Cancer Institute Clinical Pharmacology Laboratory, Duke University Medical Center, Durham, NC, USA

    Ivan Spasojevic

Authors
  1. Christine M. Walko
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  2. Austin J. Combest
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  8. Delma Armstrong
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  9. Lisa Carey
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Corresponding author

Correspondence to Christine M. Walko.

Additional information

ClinicalTrials.gov Id: NCT00719173.

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Walko, C.M., Combest, A.J., Spasojevic, I. et al. The effect of aprepitant and race on the pharmacokinetics of cyclophosphamide in breast cancer patients. Cancer Chemother Pharmacol 69, 1189–1196 (2012). https://doi.org/10.1007/s00280-011-1815-5

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  • DOI: https://doi.org/10.1007/s00280-011-1815-5

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