Advertisement

Clinical Pharmacokinetics

, Volume 58, Issue 3, pp 299–308 | Cite as

Therapeutic Drug Monitoring of Oral Anti-Hormonal Drugs in Oncology

  • Stefanie L. GroenlandEmail author
  • Merel van Nuland
  • Remy B. Verheijen
  • Jan H. M. Schellens
  • Jos H. Beijnen
  • Alwin D. R. Huitema
  • Neeltje Steeghs
Review Article

Abstract

Oral anti-hormonal drugs are essential in the treatment of breast and prostate cancer. It is well known that the interpatient variability in pharmacokinetic exposure is high for these agents and exposure–response relationships exist for many oral anti-hormonal drugs. Yet, they are still administered at fixed doses. This could lead to underdosing and thus suboptimal efficacy in some patients, while other patients could be overdosed resulting in unnecessary side effects. Therapeutic drug monitoring (TDM), individualized dosing based on measured blood concentrations of the drug, could therefore be a valid option to further optimize treatment. In this review, we provide an overview of relevant clinical pharmacokinetic and pharmacodynamic characteristics of oral anti-hormonal drugs in oncology and translate these into practical guidelines for TDM. For some agents, TDM targets are not well established yet and as a reference the median pharmacokinetic exposure could be targeted (exemestane: minimum plasma concentration (Cmin) 4.1 ng/mL and enzalutamide: Cmin 11.4 mg/L). However, for most drugs, exposure–efficacy analyses could be translated into specific targets (abiraterone: Cmin 8.4 ng/mL, anastrozole: Cmin 34.2 ng/mL, and letrozole: Cmin 85.6 ng/mL). Moreover, prospective clinical trials have shown TDM to be feasible for tamoxifen, for which the exposure–efficacy threshold of its active metabolite endoxifen is 5.97 ng/mL. Based on the available data, we therefore conclude that individualized dosing based on drug concentrations is feasible and promising for oral anti-hormonal drugs and should be developed further and implemented into clinical practice.

Notes

Compliance with Ethical Standards

Funding

No funding was received for the preparation of this article.

Conflict of interest

Remy B. Verheijen is currently a full-time employee of AstraZeneca, Cambridge, UK. Although Jan H. M. Schellens is involved in Modra Pharmaceuticals, this article does not contain information that poses a conflict of interest as it does not examine any product of Modra Pharmaceuticals or products related to this spinout company. Stefanie L. Groenland, Merel van Nuland, Jos H. Beijnen, Alwin D. R. Huitema, and Neeltje Steeghs have no conflicts of interest directly relevant to the content of this article.

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2016;66:7–30.Google Scholar
  2. 2.
    Committee for Medicinal Products for Human Use European Medicines Agency. Abiraterone European public assessment report. 2011. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002321/WC500112858.pdf. Accessed 26 May 2018.
  3. 3.
    Verheijen R, Yu H, Schellens J, Beijnen J, Steeghs N, Huitema A. Practical recommendations for therapeutic drug monitoring of kinase inhibitors in oncology. Clin Pharmacol Ther. 2017;102:765–76.Google Scholar
  4. 4.
    Yu H, Steeghs N, Nijenhuis C, Schellens J, Beijnen J, Huitema A. Practical guidelines for therapeutic drug monitoring of anticancer tyrosine kinase inhibitors: focus on the pharmacokinetic targets. Clin Pharmacokinet. 2014;53:305–25.Google Scholar
  5. 5.
    Beumer JH. Without therapeutic drug monitoring, there is no personalized cancer care. Clin Pharmacol Ther. 2013;93:228–30.Google Scholar
  6. 6.
    Paci A, Veal G, Bardin C, Levêque D, Widmer N, Beijnen J, et al. Review of therapeutic drug monitoring of anticancer drugs part 1: cytotoxics. Eur J Cancer. 2014;50:2010–9.Google Scholar
  7. 7.
    Widmer N, Bardin C, Chatelut E, Paci A, Beijnen J, Levêque D, et al. Review of therapeutic drug monitoring of anticancer drugs part two: targeted therapies. Eur J Cancer. 2014;50:2020–36.Google Scholar
  8. 8.
    Fox P, Balleine RL, Lee C, Gao B, Balakrishnar B, Menzies AM, et al. Dose escalation of tamoxifen in patients with low endoxifen level: evidence for therapeutic drug monitoring: the TADE study. Clin Cancer Res. 2016;22:3164–71.Google Scholar
  9. 9.
    De Wit D, Guchelaar HJ, Den Hartigh J, Gelderblom H, Van Erp NP. Individualized dosing of tyrosine kinase inhibitors: are we there yet? Drug Discov Today. 2015;20:18–36.Google Scholar
  10. 10.
    US Food and Drug Administration. Center for Drug Evaluation and Research. Abiraterone clinical pharmacology and biopharmaceutics review. 2011. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000ClinPharmR.pdf. Accessed 26 May 2018.
  11. 11.
    James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377:338–51.Google Scholar
  12. 12.
    Chi KN, Spratlin J, Kollmannsberger C, North S, Pankras C, Gonzalez M, et al. Food effects on abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration-resistant prostate cancer. J Clin Pharmacol. 2015;55:1406–14.Google Scholar
  13. 13.
    Carton E, Noe G, Huillard O, Golmard L, Giroux J, Cessot A, et al. Relation between plasma trough concentration of abiraterone and prostate-specific antigen response in metastatic castration-resistant prostate cancer patients. Eur J Cancer. 2017;72:54–61.Google Scholar
  14. 14.
    Stuyckens K, Saad F, Xu XS, Ryan CJ, Smith MR, Griffin TW, et al. Population pharmacokinetic analysis of abiraterone in chemotherapy-naïve and docetaxel-treated patients with metastatic castration-resistant prostate cancer. Clin Pharmacokinet. 2014;53:1149–60.Google Scholar
  15. 15.
    Attard G, Reid AHM, Yap TA, Raynaud F, Dowsett M, Settatree S, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26:4563–71.Google Scholar
  16. 16.
    Steven X, Charles X, Kim JR, Matthew S, Saad F, Griffin TW, et al. Modeling the relationship between exposure to abiraterone and prostate-specific antigen dynamics in patients with metastatic castration-resistant prostate cancer. Clin Pharmacokinet. 2017;56:55–63.Google Scholar
  17. 17.
    Li Z, Bishop AC, Alyamani M, Garcia JA, Dreicer R, Bunch D, et al. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature. 2015;523:347–51.Google Scholar
  18. 18.
    Emamekhoo H, Li Z, Sharifi N. Clinical significance of D4A in prostate cancer therapy with abiraterone. Cell Cycle. 2015;14:3213–4.Google Scholar
  19. 19.
    US Food and Drug Administration. Center for Drug Evaluation and Research. Enzalutamide clinical pharmacology and biopharmaceutics review. 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203415Orig1s000ClinPharmR.pdf. Accessed 26 May 2018.
  20. 20.
    Gibbons JA, Ouatas T, Krauwinkel W, Ohtsu Y, van der Walt J-S, Beddo V, et al. Clinical pharmacokinetic studies of enzalutamide. Clin Pharmacokinet. 2015;54:1043–55.Google Scholar
  21. 21.
    Scher HI, Anand A, Rathkopf D, Shelkey J, Morris MJ, Danila DC, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010;375:1437–46.Google Scholar
  22. 22.
    Armstrong AJ, Saad F, Phung D, Dmuchowski C, Shore ND, Fizazi K, et al. Clinical outcomes and survival surrogacy studies of prostate-specific antigen declines following enzalutamide in men with metastatic castration-resistant prostate cancer previously treated with docetaxel. Cancer. 2017;123:2303–11.Google Scholar
  23. 23.
    de Vries Schultink AHM, Zwart W, Linn SC, Beijnen JH, Huitema ADR. Effects of pharmacogenetics on the pharmacokinetics and pharmacodynamics of tamoxifen. Clin Pharmacokinet. 2015;54:797–810.Google Scholar
  24. 24.
    Jager NGL, Rosing H, Schellens JHM, Linn SC, Beijnen JH. Tamoxifen dose and serum concentrations of tamoxifen and six of its metabolites in routine clinical outpatient care. Breast Cancer Res Treat. 2014;143:477–83.Google Scholar
  25. 25.
    Borges S, Desta Z, Li L, Skaar TC, Ward BA, Nguyen A, et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther. 2006;80:61–74.Google Scholar
  26. 26.
    Mürdter TE, Schroth W, Bacchus-Gerybadze L, Winter S, Heinkele G, Simon W, et al. Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma. Clin Pharmacol Ther. 2011;89:1–10.Google Scholar
  27. 27.
    Jager N, Koornstra R, Vincent A, van Schaik R, Huitema A, Korse C, et al. Hot flashes are not predictive for serum concentrations of tamoxifen and its metabolites. BMC Cancer. 2013;13:612.Google Scholar
  28. 28.
    Madlensky L, Natarajan L, Tchu S, Pu M, Mortimer J, Flatt SW, et al. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther. 2011;89:718–25.Google Scholar
  29. 29.
    de Vries Schultink AHM, Alexi X, van Werkhoven E, Madlensky L, Natarajan L, Flatt SW, et al. An antiestrogenic activity score for tamoxifen and its metabolites is associated with breast cancer outcome. Breast Cancer Res Treat. 2017;161(3):567–74.Google Scholar
  30. 30.
    Neven P, Jongen L, Lintermans A, Van Asten K, Blomme C, Lambrechts D, et al. Tamoxifen metabolism and efficacy in breast cancer: a prospective multicentre trial. Clin Cancer Res. 2018;24(10):2312–8.Google Scholar
  31. 31.
    Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005;97:30–9.Google Scholar
  32. 32.
    Dezentje V, den Hartigh J, Guchelaar H, Hessing T, van der Straaten T, Vletter-Bogaartz J. Association between endoxifen serum concentration and predicted CYP2D6 phenotype in a prospective cohort of patients with early-stage breast cancer. J Clin Oncol. 2011;15(Suppl.):562.Google Scholar
  33. 33.
    US Food and Drug Administration. Center for Drug Evaluation and Research. Anastrozole clinical pharmacology and biopharmaceutics review. 2000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/20-541S006_Arimidex_biopharmr.pdf. Accessed 26 May 2018.
  34. 34.
    US Food and Drug Administration. Center for Drug Evaluation and Research. Letrozole clinical pharmacology and biopharmaceutics review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/20726_FEMARA 2.5MG_BIOPHARMR.PDF. Accessed 26 May 2018.
  35. 35.
    US Food and Drug Administration. Center for Drug Evaluation and Research. Exemestane clinical pharmacology and biopharmaceutics review. 1999. https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20-753_Aromasin_biopharmr_P1.pdf. Accessed 26 May 2018.
  36. 36.
    Kelly CM, Buzdar AU. Anastrozole. Expert Opin Drug Saf. 2010;9:995–1003.Google Scholar
  37. 37.
    Pauwels S, Lintermans A, Neven P, Verhaeghe J, Jans I, Billen J, et al. Need for estradiol assays with a lower functional sensitivity in clinical studies examining postmenopausal women treated with aromatase inhibitors. J Clin Oncol. 2013;31:509.Google Scholar
  38. 38.
    Ketha H, Girtman A, Singh RJ. Estradiol assays: the path ahead. Steroids. 2015;99:39–44.Google Scholar
  39. 39.
    Ingle JN, Buzdar AU, Schaid DJ, Goetz MP, Batzler A, Robson ME, et al. Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer. Cancer Res. 2010;70:3278–86.Google Scholar
  40. 40.
    Folkerd EJ, Dixon JM, Renshaw L, A’Hern RP, Dowsett M. Suppression of plasma estrogen levels by letrozole and anastrozole is related to body mass index in patients with breast cancer. J Clin Oncol. 2012;30:2977–80.Google Scholar
  41. 41.
    Oberguggenberger A, Meraner V, Sztankay M, Beer B, Weigel G, Oberacher H, et al. Can we use gonadotropin plasma concentration as surrogate marker for BMI-related incomplete estrogen suppression in breast cancer patients receiving anastrozole? BMC Cancer. 2017;17:1–7.Google Scholar
  42. 42.
    Ingle JN, Kalari KR, Buzdar AU, Robson ME, Goetz MP, Desta Z, et al. Estrogens and their precursors in postmenopausal women with early breast cancer receiving anastrozole. Steroids. 2015;99:32–8.Google Scholar
  43. 43.
    Micheal F, Saranya S, Aparna N, Sridevi N, Chithra R, Judith MP. Concepts of bioequivalence and its impact on truncated area under curve (AUC) of drugs with long half life in point estimate and intra-subject variability. J Pharm Sci Res. 2012;4:1890–6.Google Scholar
  44. 44.
    Plourde P, Dyroff M, Dukes M. Arimidex: a potent and selective fourth-generation aromatase inhibitor. Breast Cancer Res Treat. 1994;30:103–11.Google Scholar
  45. 45.
    Geisler J, King N, Dowsett M, Ottestad L, Lundgren S, Walton P, et al. Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer. Br J Cancer. 1996;74:1286–91.Google Scholar
  46. 46.
    Mandic S, Kratzsch J, Mandic D, Debeljak Z, Lukic I, Horvat V, et al. Falsely elevated serum oestradiol due to exemestane therapy. Ann Clin Biochem. 2017;54(3):402–5.Google Scholar
  47. 47.
    Hertz DL, Kidwell KM, Seewald NJ, Gersch CL, Desta Z, Flockhart DA, et al. Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer. Pharmacogenom J. 2017;17(6):521–7.Google Scholar
  48. 48.
    Hertz DL, Speth KA, Kidwell KM, Gersch CL, Desta Z, Storniolo AM, et al. Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients. Breast Cancer Res Treat. 2017;165(3):659–68.Google Scholar
  49. 49.
    Wang Y, Chia Y, Nedelman J, Schran H, Mahon F, Molimard M. A therapeutic drug monitoring algorithm for refining the imatinib trough level obtained at different sampling times. Ther Drug Monit. 2009;31:579–84.Google Scholar
  50. 50.
    Desta Z, Kreutz Y, Nguyen AT, Li L, Skaar T, Kamdem LK, et al. Plasma letrozole concentrations in postmenopausal women with breast cancer are associated with CYP2A6 genetic variants, body mass index, and age. Clin Pharmacol Ther. 2011;90:693–700.Google Scholar
  51. 51.
    De Jonge ME, Huitema ADR, Schellens JHM, Rodenhuis S, Beijnen JH. Individualised cancer chemotherapy: strategies and performance of prospective studies on therapeutic drug monitoring with dose adaptation: a review. Clin Pharmacokinet. 2005;44:147–73.Google Scholar
  52. 52.
    US Food and Drug Administration. Center for Drug Evaluation and Research. Guidance for industry: exposure–response relationships: study design, data analysis and regulatory applications. FDA Guide. 2003;1–25. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm072109.pdf.
  53. 53.
    van Nuland M, Hillebrand MJX, Rosing H, Schellens JHM, Beijnen JH. Development and validation of an LC–MS/MS method for the simultaneous quantification of abiraterone, enzalutamide, and their major metabolites in human plasma. Ther Drug Monit. 2017;39:243–51.Google Scholar
  54. 54.
    de Krou S, Rosing H, Nuijen B, Schellens JHM, Beijnen JH. Fast and adequate liquid chromatography-tandem mass spectrometric determination of Z-endoxifen serum levels for terapeutic drug monitoring. Ther Drug Monit. 2017;39:132–7.Google Scholar
  55. 55.
    van Nuland M, Rosing H, de Vries J, Ovaa H, Schellens JHM, Beijnen JH. An LC–MS/MS method for quantification of the active abiraterone metabolite Δ(4)-abiraterone (D4A) in human plasma. J Chromatogr B Anal Technol Biomed Life Sci. 2017;1068–10699:119–24.Google Scholar
  56. 56.
    Shao R, Yu L, Lou H, Ruan Z, Jiang B, Chen J. Development and validation of a rapid LC–MS/MS method to quantify letrozole in human plasma and its application to therapeutic drug monitoring. Biomed Chromatogr. 2016;30:632–7.Google Scholar
  57. 57.
    Yu J, He J, Zhang Y, Qin F, Xiong Z, Li F. Development of a liquid chromatography–tandem mass spectrometry method for determination of butoconazole nitrate in human plasma and its application to a pharmacokinetic study. Biomed Chromatogr. 2011;25:511–6.Google Scholar
  58. 58.
    Wang L-Z, Goh S-H, Wong AL-A, Thuya W-L, Lau J-YA, Wan S-C, et al. Validation of a rapid and sensitive LC–MS/MS method for determination of exemestane and its metabolites, 17beta-hydroxyexemestane and 17beta-hydroxyexemestane-17-O-beta-d-glucuronide: application to human pharmacokinetics study. PLoS One. 2015;10(3):e0118553.Google Scholar
  59. 59.
    Cardoso E, Csajka C, Schneider MP, Widmer N. Effect of adherence on pharmacokinetic/pharmacodynamic relationships of oral targeted anticancer drugs. Clin Pharmacokinet. 2018;57(1):1–6.Google Scholar
  60. 60.
    Gervasini G, Jara C, Olier C, Romero N, Martinez R, Carrillo JA. Polymorphisms in ABCB1 and CYP19A1 genes affect anastrozole plasma concentrations and clinical outcomes in postmenopausal breast cancer patients. Br J Clin Pharmacol. 2017;83:562–71.Google Scholar
  61. 61.
    Dowsett M, Cuzick J, Howell A. Jackson I; ATAC Trialists’ Group. Pharmacokinetics of anastrozole and tamoxifen alone, and in combination, during adjuvant endocrine therapy for early breast cancer in postmenopausal women: a sub-protocol of the “Arimidex™ and tamoxifen alone or in combination” (ATAC) trial. Br J Cancer. 2001;85:317–24.Google Scholar
  62. 62.
    Hubalek M, Oberguggenberger A, Beer B, Meraner V, Sztankay M, Oberacher H, et al. Does obesity interfere with anastrozole treatment? Positive association between body mass index and anastrozole plasma levels. Clin Breast Cancer. 2014;14:291–6.Google Scholar
  63. 63.
    Committee for Medicinal Products for Human Use European Medicines Agency. Public assessment report: scientific discussion exemestane. 2010. https://db.cbg-meb.nl/Pars/h104327.pdf%0A. Accessed 26 May 2018.
  64. 64.
    Bisagni G, Cocconi G, Scaglione F, Fraschini F, Pfister C, Trunet PF. Letrozole, a new oral non-steroidal aromatase inhibitor in treating postmenopausal patients with advanced breast cancer: a pilot study. Ann Oncol. 1996;7:99–102.Google Scholar
  65. 65.
    Binkhorst L, Kloth JSL, de Wit AS, de Bruijn P, Lam MH, Chaves I, et al. Circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients. Breast Cancer Res Treat. 2015;152:119–28.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Stefanie L. Groenland
    • 1
    Email author
  • Merel van Nuland
    • 2
  • Remy B. Verheijen
    • 2
  • Jan H. M. Schellens
    • 1
    • 3
  • Jos H. Beijnen
    • 2
    • 3
  • Alwin D. R. Huitema
    • 2
    • 4
  • Neeltje Steeghs
    • 1
  1. 1.Division of Medical Oncology, Department of Clinical PharmacologyThe Netherlands Cancer Institute-Antoni van LeeuwenhoekAmsterdamThe Netherlands
  2. 2.Department of Pharmacy and PharmacologyThe Netherlands Cancer Institute-Antoni van Leeuwenhoek and MC SlotervaartAmsterdamThe Netherlands
  3. 3.Department of Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
  4. 4.Department of Clinical Pharmacy, University Medical CenterUtrecht UniversityUtrechtThe Netherlands

Personalised recommendations