Clinical Pharmacokinetics

, Volume 57, Issue 1, pp 1–6 | Cite as

Effect of Adherence on Pharmacokinetic/Pharmacodynamic Relationships of Oral Targeted Anticancer Drugs

  • Evelina Cardoso
  • Chantal Csajka
  • Marie P. Schneider
  • Nicolas WidmerEmail author
Current Opinion


The emergence of oral targeted anticancer agents transformed several cancers into chronic conditions with a need for long-term oral treatment. Although cancer is a life-threatening condition, oncology medication adherence—the extent to which a patient follows the drug regimen that is intended by the prescriber—can be suboptimal in the long term, as in any other chronic disease. Poor adherence can impact negatively on clinical outcomes, notably because most of these drugs are given as a standard non-individualized dosage despite marked inter-individual variabilities that can lead to toxic or inefficacious drug concentrations. This has been especially studied with the prototypal drug imatinib. In the context of therapeutic drug monitoring (TDM), increasingly advocated for oral anticancer treatment optimization, unreported suboptimal adherence affecting drug intake history may lead to significant bias in the concentration interpretation and inappropriate dosage adjustments. In the same way, suboptimal adherence may also bias the results of pharmacokinetic modeling studies, which will affect in turn Bayesian TDM interpretation that relies on such population models. Detailed knowledge of the influence of adherence on plasma concentrations in pharmacokinetic studies or in routine TDM programs is however presently missing in the oncology field. Studies on this topic are therefore eagerly awaited to better pilot the treatment of cancer with the new targeted agents and to find their optimal dosage regimen. Hence, the development and assessment of effective medication adherence programs are warranted for these treatments.


Compliance with Ethical Standards


No funding was provided for the preparation of this article.

Conflict of interest

Evelina Cardoso, Chantal Csajka, Marie P. Schneider, and Nicolas Widmer have no conflicts of interest directly relevant to the contents of this article.


  1. 1.
    Jabbour EJ, Kantarjian H, et al. Patient adherence to tyrosine kinase inhibitor therapy in chronic myeloid leukemia. Am J Hematol. 2012;87(7):687–91.CrossRefPubMedGoogle Scholar
  2. 2.
    Levitzki A, Mishani E. Tyrphostins and other tyrosine kinase inhibitors. Annu Rev Biochem. 2006;75:93–109.CrossRefPubMedGoogle Scholar
  3. 3.
    Horne SD, Stevens JB, et al. Why imatinib remains an exception of cancer research. J Cell Physiol. 2013;228(4):665–70.CrossRefPubMedGoogle Scholar
  4. 4.
    Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009;27(13):2278–87.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Davies H, Bignell GR, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.CrossRefPubMedGoogle Scholar
  6. 6.
    Vrijens B, De Geest S, et al. A new taxonomy for describing and defining adherence to medications. Br J Clin Pharmacol. 2012;73(5):691–705.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kardas P, Lewek P, et al. Determinants of patient adherence: a review of systematic reviews. Front Pharmacol. 2013;4:91.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    World Health Organization. Adherence to long-term therapies: evidence for action. Geneva: World Health Organization; 2003.Google Scholar
  9. 9.
    Geynisman DM, Wickersham KE. Adherence to targeted oral anticancer medications. Discov Med. 2013;15(83):231–41.PubMedGoogle Scholar
  10. 10.
    Timmers L, Boons CC, et al. Adherence, exposure and patients’ experiences with the use of erlotinib in non-small cell lung cancer. J Cancer Res Clin Oncol. 2015;141(8):1481–91.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Font R, Espinas JA, et al. Prescription refill, patient self-report and physician report in assessing adherence to oral endocrine therapy in early breast cancer patients: a retrospective cohort study in Catalonia, Spain. Br J Cancer. 2012;107(8):1249–56.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Ruddy K, Mayer E, et al. Patient adherence and persistence with oral anticancer treatment. CA Cancer J Clin. 2009;59(1):56–66.CrossRefPubMedGoogle Scholar
  13. 13.
    Murphy CC, Bartholomew LK, et al. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. Breast Cancer Res Treat. 2012;134(2):459–78.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Myrick ME, Schmid SM, et al. Eligibility, compliance and persistence of extended adjuvant endocrine therapy for breast cancer. Acta Oncol. 2012;51(2):247–53.CrossRefPubMedGoogle Scholar
  15. 15.
    Cluze C, Rey D, et al. Adjuvant endocrine therapy with tamoxifen in young women with breast cancer: determinants of interruptions vary over time. Ann Oncol. 2012;23(4):882–90.CrossRefPubMedGoogle Scholar
  16. 16.
    Makubate B, Donnan PT, et al. Cohort study of adherence to adjuvant endocrine therapy, breast cancer recurrence and mortality. Br J Cancer. 2013;108(7):1515–24.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hershman DL, Shao T, et al. Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat. 2011;126(2):529–37.CrossRefPubMedGoogle Scholar
  18. 18.
    Sheppard VB, Faul LA, et al. Frailty and adherence to adjuvant hormonal therapy in older women with breast cancer: CALGB protocol 369901. J Clin Oncol. 2014;32(22):2318–27.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Lee HS, Lee JY, et al. Low adherence to upfront and extended adjuvant letrozole therapy among early breast cancer patients in a clinical practice setting. Oncology. 2014;86(5–6):340–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Noens L, van Lierde MA, et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood. 2009;113(22):5401–11.CrossRefPubMedGoogle Scholar
  21. 21.
    Marin D, Bazeos A, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010;28(14):2381–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Ibrahim AR, Eliasson L, et al. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood. 2011;117(14):3733–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Branford S, Yeung DT, et al. BCR-ABL1 doubling times more reliably assess the dynamics of CML relapse compared with the BCR-ABL1 fold rise: implications for monitoring and management. Blood. 2012;119(18):4264–71.CrossRefPubMedGoogle Scholar
  24. 24.
    Breccia M, Efficace F, et al. Adherence and future discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia: a patient-based survey on 1133 patients. Leuk Res. 2015;39(10):1055–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Rychter A, Jerzmanowski P, et al. Treatment adherence in chronic myeloid leukaemia patients receiving tyrosine kinase inhibitors. Med Oncol. 2017;34(6):104.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Krummenacher I, Cavassini M, et al. An interdisciplinary HIV-adherence program combining motivational interviewing and electronic antiretroviral drug monitoring. AIDS Care. 2011;23(5):550–61.CrossRefPubMedGoogle Scholar
  27. 27.
    Lelubre M, Kamal S, et al. Interdisciplinary medication adherence program: the example of a university community pharmacy in Switzerland. BioMed Res Int. 2015;2015:103546.CrossRefPubMedGoogle Scholar
  28. 28.
    de Bruin M, Oberje EJM, et al. Effectiveness and cost-effectiveness of a nurse-delivered intervention to improve adherence to treatment for HIV: a pragmatic, multicentre, open-label, randomised clinical trial. Lancet Infect Dis. 2017;17(6):595–604.CrossRefPubMedGoogle Scholar
  29. 29.
    Verbrugghe M, Duprez V, et al. Factors influencing adherence in cancer patients taking oral tyrosine kinase inhibitors: a qualitative study. Cancer Nurs. 2016;39(2):153–62.CrossRefPubMedGoogle Scholar
  30. 30.
    Mathes T, Antoine SL, et al. Adherence enhancing interventions for oral anticancer agents: a systematic review. Cancer Treat Rev. 2014;40(1):102–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Santoleri F, Lasala R, et al. Medication adherence to tyrosine kinase inhibitors: 2-year analysis of medication adherence to imatinib treatment for chronic myeloid leukemia and correlation with the depth of molecular response. Acta Haematol. 2016;136(1):45–51.CrossRefPubMedGoogle Scholar
  32. 32.
    von Mehren M, Widmer N. Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): an emerging role for drug blood level testing? Cancer Treat Rev. 2011;37(4):291–9.CrossRefGoogle Scholar
  33. 33.
    Di Bella NJ, Bhowmik D, et al. The effectiveness of tyrosine kinase inhibitors and molecular monitoring patterns in newly diagnosed patients with chronic myeloid leukemia in the community setting. Clin Lymphoma Myeloma Leuk. 2015;15(10):599–605.CrossRefPubMedGoogle Scholar
  34. 34.
    Barthelemy P, Asmane-De la Porte I, et al. Adherence and patients’ attitudes to oral anticancer drugs: a prospective series of 201 patients focusing on targeted therapies. Oncology. 2015;88(1):1–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Gonzalez JS, Batchelder AW, et al. Depression and HIV/AIDS treatment nonadherence: a review and meta-analysis. J Acquir Immune Defic Syndr. 2011;58(2):181–7.CrossRefPubMedGoogle Scholar
  36. 36.
    de Wit D, Guchelaar HJ, et al. Individualized dosing of tyrosine kinase inhibitors: are we there yet? Drug Discov Today. 2015;20(1):18–36.CrossRefPubMedGoogle Scholar
  37. 37.
    Mathijssen RH, Sparreboom A, et al. Determining the optimal dose in the development of anticancer agents. Nat Rev Clin Oncol. 2014;11(5):272–81.CrossRefPubMedGoogle Scholar
  38. 38.
    Bardin C, Veal G, et al. Therapeutic drug monitoring in cancer: are we missing a trick? Eur J Cancer. 2014;50(12):2005–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Fletcher CV, Testa MA, et al. Four measures of antiretroviral medication adherence and virologic response in AIDS clinical trials group study 359. J Acquir Immune Defic Syndr. 2005;40(3):301–6.CrossRefPubMedGoogle Scholar
  40. 40.
    Fayet Mello A, Buclin T, et al. Successful efavirenz dose reduction guided by therapeutic drug monitoring. Antivir Ther. 2011;16(2):189–97.CrossRefPubMedGoogle Scholar
  41. 41.
    Podsadecki TJ, Vrijens BC, et al. “White coat compliance” limits the reliability of therapeutic drug monitoring in HIV-1-infected patients. HIV Clin Trials. 2008;9(4):238–46.CrossRefPubMedGoogle Scholar
  42. 42.
    Rowland A, van Dyk M, et al. Kinase inhibitor pharmacokinetics: comprehensive summary and roadmap for addressing inter-individual variability in exposure. Expert Opin Drug Metab Toxicol. 2017;13(1):31–49.CrossRefPubMedGoogle Scholar
  43. 43.
    Ling J, Fettner S, et al. Effect of food on the pharmacokinetics of erlotinib, an orally active epidermal growth factor receptor tyrosine-kinase inhibitor, in healthy individuals. Anticancer Drugs. 2008;19(2):209–16.CrossRefPubMedGoogle Scholar
  44. 44.
    Achtari Jeanneret L, Lüthi F, et al. Adhésion thérapeutique aux traitements oncologiques oraux et prise en charge interdisciplinaire. Rev Med Suisse. 2011;7(296)1154–8, 1160.Google Scholar
  45. 45.
    Fuchs A, Rotzinger A, et al. Comparison of population pharmacokinetics based on steady-state assumption versus electronically monitored adherence to lopinavir, atazanavir, efavirenz, and etravirine: a retrospective study. Ther Drug Monit. 2016;38(4):506–15.CrossRefPubMedGoogle Scholar
  46. 46.
    Hénin E, Tod M, et al. Pharmacokinetically based estimation of patient compliance with oral anticancer chemotherapies: in silico evaluation. Clin Pharmacokinet. 2009;48(6):359–69.CrossRefPubMedGoogle Scholar
  47. 47.
    Barrière O, Li J, et al. A Bayesian approach for the estimation of patient compliance based on the last sampling information. J Pharmacokinet Pharmacodyn. 2011;38(3):333–51.CrossRefPubMedGoogle Scholar
  48. 48.
    Eechoute K, Fransson MN, et al. A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients. Clin Cancer Res. 2012;18(20):5780–7.CrossRefPubMedGoogle Scholar
  49. 49.
    Judson I, Peiming M, et al. Imatinib pharmacokinetics in patients with gastrointestinal stromal tumour: a retrospective population pharmacokinetic study over time. EORTC Soft Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol. 2005;55(4):379–86.CrossRefPubMedGoogle Scholar
  50. 50.
    Chatelut E, Gandia P, et al. Long-term prospective population PK study in GIST patients [letter]. Clin Cancer Res. 2013;19(4):949.CrossRefPubMedGoogle Scholar
  51. 51.
    Farag S, Verheijen RB, et al. Imatinib pharmacokinetics in a large observational cohort of gastrointestinal stromal tumour patients. Clin Pharmacokinet. 2017;56(3):287–92.CrossRefPubMedGoogle Scholar
  52. 52.
    Bins S, Eechoute K, et al. Prospective analysis in GIST patients on the role of alpha-1 acid glycoprotein in imatinib exposure. Clin Pharmacokinet. 2016;56(3):305–10.CrossRefPubMedCentralGoogle Scholar
  53. 53.
    Arrondeau J, Mir O, et al. Sorafenib exposure decreases over time in patients with hepatocellular carcinoma. Invest New Drugs. 2012;30(5):2046–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.School of Pharmaceutical SciencesUniversity of Geneva, University of LausanneGenevaSwitzerland
  2. 2.Community Pharmacy, Department of Ambulatory Care and Community MedicineUniversity of LausanneLausanneSwitzerland
  3. 3.Pharmacy of Eastern Vaud HospitalsVeveySwitzerland
  4. 4.Division of Clinical Pharmacology, Service of BiomedicineLausanne University HospitalLausanneSwitzerland

Personalised recommendations