Clinical Pharmacokinetics

, Volume 48, Issue 6, pp 359–369 | Cite as

Pharmacokinetically Based Estimation of Patient Compliance with Oral Anticancer Chemotherapies

In Silico Evaluation
  • Emilie Hénin
  • Michel Tod
  • Véronique Trillet-Lenoir
  • Catherine Rioufol
  • Brigitte Tranchand
  • Pascal Girard
Original Research Article


Background and objectives

More and more anticancer chemotherapies are now available as oral formulations. This relatively new route of administration in oncology leads to problems with patient education and non-compliance. The aim of this study was to explore the performances of the ‘inverse problem’, namely, estimation of compliance from pharmacokinetics. For this purpose, we developed and evaluated a method to estimate patient compliance with an oral chemotherapy in silico (i) from an a priori population pharmacokinetic model; (ii) with limited optimal pharmacokinetic information collected on day 1; and (iii) from a single pharmacokinetic sample collected after multiple doses.


Population pharmacokinetic models, including estimation of all fixed and random effects estimated on a prior dataset, and sparse samples taken after the first dose, were combined to provide the individual POSTHOC Bayesian pharmacokinetic parameter estimates. Sampling times on day 1 were chosen according to a D-optimal design. Individual pharmacokinetic profiles were simulated according to various dose-taking scenarios.

To characterize compliance over the n previous dosing times (supposedly known without error), 2n different compliance scenarios of doses taken/not taken were considered. The observed concentration value was compared with concentrations predicted from the model and each compliance scenario. To discriminate between different compliance profiles, we used the Euclidean distance between the observed pharmacokinetic values and the predicted values simulated without residual errors.

This approach was evaluated in silico and applied to imatinib and capecitabine, the pharmacokinetics of which are described in the literature, and which have quite different pharmacokinetic characteristics (imatinib has an elimination half-life of 17 hours, and α-fluoro-β-alanine [FBAL], the metabolite of capecitabine, has an elimination half-life of 3 hours). 1000 parameter sets were drawn according to population distributions, and concentration values were simulated at several timepoints under various compliance patterns to compare with the predicted ones. In addition, several simulation scenarios were run in order to explore the impact of the quality of the error model, interoccasion variability (IOV), error in the number of pills taken, and the performance of the compliance estimation method.


The best compliance estimate was obtained with pharmacokinetic samples taken 5 hours after the last dose. Performance of the method varied between simulation scenarios. In both the imatinib and capecitabine basic simulations, patient compliance was correctly estimated on the two last scheduled doses (with better results for imatinib). The magnitude of the error model also had a great impact on the quality of the compliance estimate.


We highlight the effect of three parameters on the quality of compliance estimates based on limited pharmacokinetic information: the plasma elimination half-life, interdose interval and magnitude of the error model. Nevertheless, the pharmacokinetic method is not informative enough and should be used with electronic monitoring, which provides additional information on compliance. Our method will be used in a future phase IV clinical trial where the relationships between compliance, efficacy and tolerability will be assessed.


  1. 1.
    Liu G, Franssen E, Fitch MI, et al. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997 Jan; 15(1): 110–5PubMedGoogle Scholar
  2. 2.
    Chau I, Legge S, Fumoleau P. The vital role of education and information in patients receiving capecitabine (Xeloda®). Eur J Oncol Nurs 2004; 8(3 Suppl.): S41–53PubMedCrossRefGoogle Scholar
  3. 3.
    Gerbrecht BM, Kangas T. Implications of capecitabine (Xeloda®) for cancer nursing practice. Eur J Oncol Nurs 2004; 8(3 Suppl.): S63–71PubMedCrossRefGoogle Scholar
  4. 4.
    Grober SE, Carpenter RC, Glassman M, et al. A comparison of patients’ perceptions of oral cancer treatments and intravenous cancer treatments: what the health care team needs to know [abstract no. 3000]. Proc Am Soc Clin Oncol 2003; 22: 746Google Scholar
  5. 5.
    Catania C, Didier F, Sbanotto A, et al. Fully oral chemotherapy regimens: patient’s or physician’s preference [abstract no. 3122]. Proc Am Soc Clin Oncol 2003; 22: 777Google Scholar
  6. 6.
    Waterhouse DM, Calzone KA, Mele C, et al. Adherence to oral tamoxifen: a comparison of patient self-report, pill counts, and microelectronic monitoring. J Clin Oncol 1993 Jun; 11(6): 1189–97PubMedGoogle Scholar
  7. 7.
    Partridge AH, Avorn J, Wang PS, et al. Adherence to therapy with oral antineoplastic agents. J Natl Cancer Inst 2002 May 1; 94(9): 652–61PubMedCrossRefGoogle Scholar
  8. 8.
    Urquhart J, De Klerk E. Contending paradigms for the interpretation of data on patient compliance with therapeutic drug regimens. Stat Med 1998 Feb 15; 17(3): 251–67PubMedCrossRefGoogle Scholar
  9. 9.
    Zeppetella G. How do terminally ill patients at home take their medication?. Palliat Med 1999 Nov; 13(6): 469–75PubMedCrossRefGoogle Scholar
  10. 10.
    Iskedjian M, Einarson TR, MacKeigan LD, et al. Relationship between daily dose frequency and adherence to antihypertensive pharmacotherapy: evidence from a meta-analysis. Clin Ther 2002 Feb; 24(2): 302–16PubMedCrossRefGoogle Scholar
  11. 11.
    Mu S, Ludden TM. Estimation of population pharmacokinetic parameters in the presence of non-compliance. J Pharmacokinet Pharmacodyn 2003 Feb; 30(1): 53–81PubMedCrossRefGoogle Scholar
  12. 12.
    Cramer JA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed? A novel assessment technique. JAMA 1989 Jun 9; 261(22): 3273–7PubMedCrossRefGoogle Scholar
  13. 13.
    De Tullio PL, Kirking DM, Arslanian C, et al. Compliance measure development and assessment of theophylline therapy in ambulatory patients. J Clin Pharm Ther 1987 Feb; 12(1): 19–26PubMedGoogle Scholar
  14. 14.
    Jonsson EN, Wade JR, Almqvist G, et al. Discrimination between rival dosing histories. Pharm Res 1997 Aug; 14(8): 984–91PubMedCrossRefGoogle Scholar
  15. 15.
    Pullar T, Kumar S, Tindall H, et al. Time to stop counting the tablets?. Clin Pharmacol Ther 1989 Aug; 46(2): 163–8PubMedCrossRefGoogle Scholar
  16. 16.
    Urquhart J. The electronic medication event monitor: lessons for pharmacotherapy. Clin Pharmacokinet 1997 May; 32(5): 345–56PubMedCrossRefGoogle Scholar
  17. 17.
    Feldman HI, Hackett M, Bilker W, et al. Potential utility of electronic drug compliance monitoring in measures of adverse outcomes associated with immunosuppressive agents. Pharmacoepidemiol Drug Saf 1999 Jan; 8(1): 1–14PubMedCrossRefGoogle Scholar
  18. 18.
    Rudd P. In search of the gold standard for compliance measurement. Arch Intern Med 1979 Jun; 139(6): 627–8PubMedCrossRefGoogle Scholar
  19. 19.
    Levine AM, Richardson JL, Marks G, et al. Compliance with oral drug therapy in patients with hematologic malignancy. J Clin Oncol 1987 Sep; 5(9): 1469–76PubMedGoogle Scholar
  20. 20.
    Urquhart J. Role of patient compliance in clinical pharmacokinetics: a review of recent research. Clin Pharmacokinet 1994 Sep; 27(3): 202–15PubMedCrossRefGoogle Scholar
  21. 21.
    Lim LL. Estimating compliance to study medication from serum drug levels: application to an AIDS clinical trial of zidovudine. Biometrics 1992 Jun; 48(2): 619–30PubMedCrossRefGoogle Scholar
  22. 22.
    Rubio A, Cox C, Weintraub M. Prediction of diltiazem plasma concentration curves from limited measurements using compliance data. Clin Pharmacokinet 1992 Mar; 22(3): 238–46PubMedCrossRefGoogle Scholar
  23. 23.
    Pullar T, Kumar S, Chrystyn H, et al. The prediction of steady-state plasma phenobarbitone concentrations (following low-dose phenobarbitone) to refine its use as an indicator of compliance. Br J Clin Pharmacol 1991 Sep; 32(3): 329–33PubMedCrossRefGoogle Scholar
  24. 24.
    Vrijens B, Tousset E, Rode R, et al. Successful projection of the time course of drug concentration in plasma during a 1-year period from electronically compiled dosing-time data used as input to individually parameterized pharmacokinetic models. J Clin Pharmacol 2005 Apr; 45(4): 461–7PubMedCrossRefGoogle Scholar
  25. 25.
    Santschi V, Wuerzner G, Schneider MP, et al. Clinical evaluation of IDAS II, a new electronic device enabling drug adherence monitoring. Eur J Clin Pharmacol 2007 Dec; 63(12): 1179–84PubMedCrossRefGoogle Scholar
  26. 26.
    Duffull S, Denman M, Eccleston J, et al. WinPOPT user guide (version 1.1). Dunedin: University of Otago, 2006Google Scholar
  27. 27.
    Beal SL, Sheiner LB. The NONMEM system. Am Stat 1980; 34: 118–9CrossRefGoogle Scholar
  28. 28.
    Beal SL, Sheiner LB. NONMEM user’s guides. San Francisco (CA): NONMEM Project Group, University of California, 1992Google Scholar
  29. 29.
    Insightful Corporation. S-Plus 6 user’s guide. Seattle (WA): Insightful Corporation, 2002Google Scholar
  30. 30.
    Widmer N, Decosterd LA, Csajka C, et al. Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein. Br J Clin Pharmacol 2006 Jul; 62(1): 97–112PubMedCrossRefGoogle Scholar
  31. 31.
    Gieschke R, Reigner B, Blesch KS, et al. Population pharmacokinetic analysis of the major metabolites of capecitabine. J Pharmacokinet Pharmacodyn 2002 Feb; 29(1): 25–47PubMedCrossRefGoogle Scholar
  32. 32.
    Reigner B, Blesch K, Weidekamm E. Clinical pharmacokinetics of capecitabine. Clin Pharmacokinet 2001; 40(2): 85–104PubMedCrossRefGoogle Scholar
  33. 33.
    Wang W, Husan F, Chow SC. The impact of patient compliance on drug concentration profile in multiple doses. Stat Med 1996 Mar 30; 15(6): 659–69PubMedCrossRefGoogle Scholar
  34. 34.
    Girard P, Sheiner LB, Kastrissios H, et al. Do we need full compliance data for population pharmacokinetic analysis?. J Pharmacokinet Biopharm 1996 Jun; 24(3): 265–82PubMedGoogle Scholar
  35. 35.
    Li J, Nekka F. A pharmacokinetic formalism explicitly integrating the patient drug compliance. J Pharmacokinet Pharmacodyn 2007 Feb; 34(1): 115–39PubMedCrossRefGoogle Scholar
  36. 36.
    Lu J, Gries JM, Verotta D, et al. Selecting reliable pharmacokinetic data for explanatory analyses of clinical trials in the presence of possible noncompliance. J Pharmacokinet Pharmacodyn 2001 Aug; 28(4): 343–62PubMedCrossRefGoogle Scholar
  37. 37.
    Kshirsagar SA, Blaschke TF, Sheiner LB, et al. Improving data reliability using a non-compliance detection method versus using pharmacokinetic criteria. J Pharmacokinet Pharmacodyn 2007 Feb; 34(1): 35–55PubMedCrossRefGoogle Scholar
  38. 38.
    Gupta P, Hutmacher MM, Frame B, et al. An alternative method for population pharmacokinetic data analysis under noncompliance. J Pharmacokinet Pharmacodyn 2008 Apr; 35(2): 219–33PubMedCrossRefGoogle Scholar
  39. 39.
    Soy D, Beal SL, Sheiner LB. Population one-compartment pharmacokinetic analysis with missing dosage data. Clin Pharmacol Ther 2004 Nov; 76(5): 441–51PubMedCrossRefGoogle Scholar
  40. 40.
    Girard P, Blaschke TF, Kastrissios H, et al. A Markov mixed effect regression model for drug compliance. Stat Med 1998 Oct 30; 17(20): 2313–33PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Emilie Hénin
    • 1
  • Michel Tod
    • 1
  • Véronique Trillet-Lenoir
    • 1
    • 2
  • Catherine Rioufol
    • 1
    • 3
  • Brigitte Tranchand
    • 4
  • Pascal Girard
    • 1
  1. 1.Faculté de Médecine Lyon SudUniversité Lyon 1, EA3738, CTOOullinsFrance
  2. 2.Service d’Oncologie Médicale, Centre Hospitalier Lyon SudHospices Civils de LyonPierre-BéniteFrance
  3. 3.Unité de Pharmacie Clinique Oncologique, Centre Hospitalier Lyon SudHospices Civils de LyonPierre-BéniteFrance
  4. 4.Centre Léon BérardLyonFrance
  5. 5.Faculté de Médecine Lyon-SudEA 3738, CTOOullins CedexFrance

Personalised recommendations