Advertisement

Analytical and Bioanalytical Chemistry

, Volume 398, Issue 4, pp 1791–1800 | Cite as

Development and validation of a liquid chromatography–tandem mass spectrometry method for the simultaneous quantification of tamoxifen, anastrozole, and letrozole in human plasma and its application to a clinical study

  • Beate Beer
  • Birthe Schubert
  • Anne Oberguggenberger
  • Verena Meraner
  • Michael Hubalek
  • Herbert Oberacher
Original Paper

Abstract

There is substantial evidence that circulating estrogens promote the proliferation of breast cancer. Consequently, adjuvant hormonal treatment strategies targeting estrogen action have been established. Such hormonal therapies include selective estrogen receptor modulators, such as tamoxifen, which interfere at the estrogen receptors directly, or non-steroidal aromatase inhibitors, such as anastrozole and letrozole, which inhibit estrogen synthesis through blocking the aromatase, a key enzyme of estrogen production. Despite considerable therapeutic success, in several cases, the use of these drugs is limited by side effects that have been described to significantly impair the adherence of patients to endocrine treatment. However, objective data concerning patient adherence and its clinical relevance are limited. One promising approach to check patient-reported adherence is drug monitoring in human plasma. Therefore, a liquid chromatography–tandem mass spectrometry method to determine the plasma concentrations of tamoxifen, anastrozole, and letrozole has been developed and fully validated according to guidelines for clinical and forensic toxicology. The validation criteria evaluated were selectivity, linearity, accuracy and precision, limit of quantification, recovery and matrix effects, sample stability, and carryover. The six-point calibration curves showed linearity over the range of concentrations from 25 to 500 ng/ml for tamoxifen, 5 to 200 ng/ml for anastrozole, and 10 to 300 ng/ml for letrozole. The intra- and inter-day precision and accuracies were always better than 15%. The validated procedure was successfully applied to a clinical study (Patient-Reported Outcomes in Breast Cancer Patients undergoing Endocrine Therapy, PRO-BETh). A major aim of PRO-BETh study is the comprehensive evaluation of adherence to treatment in pre- and post-menopausal women with breast cancer. Plasma samples of 310 breast cancer patients undergoing anti-estrogen therapy were analyzed. Eight samples did not contain a quantifiable amount of drug, strongly indicating non-adherence of the corresponding patients to adjuvant breast cancer treatment. Furthermore, plasma concentrations at the lower end of the observed plasma level distribution might represent a hint but not a confirmation for non-adherence in terms of non-daily and irregular intake of the prescribed drug.

Keywords

LC/MS/MS Drug monitoring Adherence Tamoxifen Anastrozole Letrozole 

References

  1. 1.
    Hortobagyi GN, de la Garza SJ, Pritchard K, Amadori D, Haidinger R, Hudis CA, Khaled H, Liu MC, Martin M, Namer M, O’Shaughnessy JA, Shen ZZ, Albain KS (2005) Clin Breast Cancer 6:391CrossRefGoogle Scholar
  2. 2.
    Hiscox S, Davies EL, Barrett-Lee P (2009) Maturitas 63:275CrossRefGoogle Scholar
  3. 3.
    Choueiri TK, Alemany CA, Bou-Jawde RM, Budd GT (2004) Clin Ther 26:1199CrossRefGoogle Scholar
  4. 4.
    Eisen A, Trudeau M, Shelley W, Messersmith H, Pritchard KI (2008) Cancer Treat Rev 34:157CrossRefGoogle Scholar
  5. 5.
    Hind D, Ward S, De NE, Simpson E, Carroll C, Wyld L (2007) Health Technol Assess 11:1Google Scholar
  6. 6.
    Musgrove EA, Sutherland RL (2009) Nat Rev Cancer 9:631CrossRefGoogle Scholar
  7. 7.
    Robinson E, Kimmick GG, Muss HB (1996) Drugs Aging 8:329CrossRefGoogle Scholar
  8. 8.
    Conte P, Frassoldati A (2007) Breast J 13:28CrossRefGoogle Scholar
  9. 9.
    Perez EA (2007) Ann Oncol 18(Suppl 8):viii26Google Scholar
  10. 10.
    Demissie S, Silliman RA, Lash TL (2001) J Clin Oncol 19:322Google Scholar
  11. 11.
    Fink AK, Gurwitz J, Rakowski W, Guadagnoli E, Silliman RA (2004) J Clin Oncol 22:3309CrossRefGoogle Scholar
  12. 12.
    Partridge AH, Wang PS, Winer EP, Avorn J (2003) J Clin Oncol 21:602CrossRefGoogle Scholar
  13. 13.
    Partridge AH (2006) Ann Oncol 17:183CrossRefGoogle Scholar
  14. 14.
    Ziller V, Kalder M, Albert US, Holzhauer W, Ziller M, Wagner U, Hadji P (2009) Ann Oncol 20:431CrossRefGoogle Scholar
  15. 15.
    Chlebowski RT, Geller ML (2006) Oncology 71:1Google Scholar
  16. 16.
    Ruddy K, Mayer E, Partridge A (2009) CA Cancer J Clin 59:56CrossRefGoogle Scholar
  17. 17.
    Hadji P (2010) Crit Rev Oncol Hematol 73:156CrossRefGoogle Scholar
  18. 18.
    Larson ME, Richards TM (2009) Clin Med Res 7:134CrossRefGoogle Scholar
  19. 19.
    Van Rossum AM, Bergshoeff AS, Fraaij PL, Hugen PW, Hartwig NG, Geelen SP, Wolfs TF, Weemaes CM, de Groot R, Burger DM (2002) Pediatr Infect Dis J 21:743CrossRefGoogle Scholar
  20. 20.
    Hiemke C (2008) Eur J Clin Pharmacol 64:159CrossRefGoogle Scholar
  21. 21.
    Touw DJ, Neef C, Thomson AH, Vinks AA (2005) Ther Drug Monit 27:10CrossRefGoogle Scholar
  22. 22.
    Gjerde J, Kisanga ER, Hauglid M, Holm PI, Mellgren G, Lien EA (2005) J Chromatogr A 1082:6CrossRefGoogle Scholar
  23. 23.
    Liu W, Zhang L, Chen S, Duan H, Chen X, Wei Z, Chen G (2009) Anal Chim Acta 631:47CrossRefGoogle Scholar
  24. 24.
    Murphy C, Fotsis T, Pantzar P, Adlercreutz H, Martin F (1987) J Steroid Biochem 26:547CrossRefGoogle Scholar
  25. 25.
    Teunissen SF, Rosing H, Koornstra RH, Linn SC, Schellens JH, Schinkel AH, Beijnen JH (2009) J Chromatogr B 877:2519CrossRefGoogle Scholar
  26. 26.
    Zweigenbaum J, Heinig K, Steinborner S, Wachs T, Henion J (1999) Anal Chem 71:2294CrossRefGoogle Scholar
  27. 27.
    de Voss D, Slee PH, Briggs RJ, Stevenson D (1998) Cancer Chemother Pharmacol 42:512CrossRefGoogle Scholar
  28. 28.
    Decensi A, Gandini S, Guerrieri-Gonzaga A, Johansson H, Manetti L, Bonanni B, Sandri MT, Barreca A, Costa A, Robertson C, Lien EA (1999) J Clin Oncol 17:2633Google Scholar
  29. 29.
    Dowsett M, Cuzick J, Howell A, Jackson I (2001) Br J Cancer 85:317CrossRefGoogle Scholar
  30. 30.
    Lee KH, Ward BA, Desta Z, Flockhart DA, Jones DR (2003) J Chromatogr B 791:245CrossRefGoogle Scholar
  31. 31.
    MacCallum J, Cummings J, Dixon JM, Miller WR (1996) J Chromatogr B 678:317CrossRefGoogle Scholar
  32. 32.
    Apostolou C, Dotsikas Y, Kousoulos C, Loukas YL (2008) J Pharm Biomed Anal 48:853CrossRefGoogle Scholar
  33. 33.
    Mendes GD, Hamamoto D, Ilha J, Pereira AS, De Nucci G (2007) J Chromatogr B 850:553CrossRefGoogle Scholar
  34. 34.
    Rodriguez-Flores J, Contento Salcedo AM, Villasenor Llerena MJ, Munoz FL (2008) Electrophoresis 29:811CrossRefGoogle Scholar
  35. 35.
    Ingle JN, Buzdar AU, Schaid DJ, Goetz MP, Batzler A, Robson ME, Northfelt DW, Olson JE, Perez EA, Desta Z, Weintraub RA, Williard CV, Flockhart DA, Weinshilboum RM (2010) Cancer Res 70:3278CrossRefGoogle Scholar
  36. 36.
    Dowsett M, Pfister C, Johnston SR, Miles DW, Houston SJ, Verbeek JA, Gundacker H, Sioufi A, Smith IE (1999) Clin Cancer Res 5:2338Google Scholar
  37. 37.
    Pfister CU, Martoni A, Zamagni C, Lelli G, De Braud F, Souppart C, Duval M, Hornberger U (2001) Biopharm Drug Dispos 22:191CrossRefGoogle Scholar
  38. 38.
    Peters FT, Drummer OH, Musshoff F (2007) Forensic Sci Int 165:216CrossRefGoogle Scholar
  39. 39.
    Oberacher H, Krajete A, Parson W, Huber CG (2000) J Chromatogr A 893:23CrossRefGoogle Scholar
  40. 40.
    Matuszewski BK, Constanzer ML, Chavez-Eng CM (2003) Anal Chem 75:3019CrossRefGoogle Scholar
  41. 41.
    Dadgar D, Burnett PE (1995) J Pharm Biomed Anal 14:23CrossRefGoogle Scholar
  42. 42.
    Koster E (2005) The Peak August 2005:5Google Scholar
  43. 43.
    Oberacher H, Pavlic M, Libiseller K, Schubert B, Sulyok M, Schuhmacher R, Csaszar E, Kofeler HC (2009) J Mass Spectrom 44:485CrossRefGoogle Scholar
  44. 44.
    Oberacher H, Pavlic M, Libiseller K, Schubert B, Sulyok M, Schuhmacher R, Csaszar E, Kofeler HC (2009) J Mass Spectrom 44:494CrossRefGoogle Scholar
  45. 45.
    Pfister CU, Duval M, Godbillon J, Gosset G, Gygax D, Marfil F, Sioufi A, Winkler B (1994) J Pharm Sci 83:520CrossRefGoogle Scholar
  46. 46.
    Buzdar AU, Robertson JF, Eiermann W, Nabholtz JM (2002) Cancer 95:2006CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Beate Beer
    • 1
  • Birthe Schubert
    • 1
  • Anne Oberguggenberger
    • 2
  • Verena Meraner
    • 2
  • Michael Hubalek
    • 3
  • Herbert Oberacher
    • 1
  1. 1.Institute of Legal MedicineInnsbruck Medical UniversityInnsbruckAustria
  2. 2.Department of General and Social PsychiatryInnsbruck Medical UniversityInnsbruckAustria
  3. 3.Department of Obstetrics and GynecologyInnsbruck Medical UniversityInnsbruckAustria

Personalised recommendations