Pharmaceutical Research

, Volume 25, Issue 2, pp 359–368 | Cite as

Population Pharmacokinetic Data Analysis of Cilobradine, an If Channel Blocker

  • Gabriele Fliss
  • Alexander Staab
  • Christiane Tillmann
  • Dirk Trommeshauser
  • Hans G. Schaefer
  • Charlotte Kloft
Research Paper



To evaluate the population pharmacokinetic characteristics of cilobradine including a covariate analysis based on six phase I trials and to assess the predictive performance of the model developed.


Single or multiple doses of cilobradine were administered as solution, capsule or infusion. Two thousand, seven hundred and thirty-three plasma samples (development data set) were used for model development in NONMEM. Model evaluation was performed using also an external data set.


Data were best described by a linear three-compartment model. Typical Vss was large (∼100 l) and CL was 21.5 l/h. Covariate analysis revealed a statistically significant but clinically irrelevant relation between KA and dose. Inter-individual variability was moderate (15–46%); imprecision of estimates was generally low. The final model was successfully applied to the external data set revealing its robustness and general applicability. Its final estimates resembled those of the development data set except for the covariate relation not being supported. When excluding the covariate relation, all observations were well predicted.


A robust population PK model has been developed for cilobradine predicting plasma concentrations from a different study design well. Therefore, the model can serve as a tool to simulate and evaluate different dosing regimens for further clinical trials.

Key words

cilobradine If channel blocker NONMEM population pharmacokinetics 


  1. 1.
    E. H. Sonnenblick, J. Ross Jr., and E. Braunwald. Oxygen consumption of the heart. Newer concepts of its multifactoral determination. Am. J. Cardiol. 22(3):328–336 (1968).PubMedCrossRefGoogle Scholar
  2. 2.
    E. Braunwald. Control of myocardial oxygen consumption: physiologic and clinical considerations. Am. J. Cardiol. 27(4):416–432 (1971).PubMedCrossRefGoogle Scholar
  3. 3.
    W. H. Frishman. Beta-adrenergic blockade for the treatment of angina pectoris. In D. A. Weiner and W. H. Frishman (eds.), Therapy of Angina pectoris. A Comprehensive Guide for the Clinicians, Marcel Dekker, New York, 1986, pp. 83–144.Google Scholar
  4. 4.
    W. H. Frishman. Multifactorial actions of beta-adrenergic blocking drugs in ischemic heart disease: current concepts. Circulation 67(6 Pt 2):I11–I18 (1983).PubMedGoogle Scholar
  5. 5.
    J. W. Dammgen, K. A. Lamping, and G. J. Gross. Actions of two new bradycardic agents, AQ-AH 208 and UL-FS 49, on ischemic myocardial perfusion and function. J. Cardiovasc. Pharmacol. 7(1):71–79 (1985).PubMedCrossRefGoogle Scholar
  6. 6.
    G. Krumpl, W. Schneider, and G. Raberger. Can exercise-induced regional contractile dysfunction be prevented by selective bradycardic agents? Naunyn Schmiedebergs Arch. Pharmacol. 334(4):540–543 (1986).PubMedCrossRefGoogle Scholar
  7. 7.
    W. Kobinger and C. Lillie. Specific bradycardic agents—a novel pharmacological class? Eur. Heart J. 8(Suppl L):7–15 (1987).PubMedGoogle Scholar
  8. 8.
    P. P. van Bogaert and M. Goethals. Pharmacological influence of specific bradycardic agents on the pacemaker current of sheep cardiac Purkinje fibres. A comparison between three different molecules. Eur. Heart J. 8(Suppl L):35–42 (1987).PubMedGoogle Scholar
  9. 9.
    P. P. van Bogaert and F. Pittoors. Use-dependent blockade of cardiac pacemaker current (If) by cilobradine and zatebradine. Eur. J. Pharmacol. 478(2–3):161–171 (2003).PubMedCrossRefGoogle Scholar
  10. 10.
    R. Schulz, J. Rose, A. Skyschally, and G. Heusch. Bradycardic agent UL-FS 49 attenuates ischemic regional myocardial dysfunction and reduces infarct size in swine: comparison with the beta-blocker atenolol. J. Cardiovasc. Pharmacol. 25(2):216–228 (1995).PubMedCrossRefGoogle Scholar
  11. 11.
    W. Kobinger, C. Lillie, and L. Pichler. Cardiovascular actions of N-allyl-clonidine (ST 567), a substance with specific bradycardic action. Eur. J. Pharmacol. 58(2):141–150 (1979).PubMedCrossRefGoogle Scholar
  12. 12.
    J. Dammgen, R. Kadatz, and W. Diederen. Cardiovascular actions of 5,6-dimethoxy-2-(3-[(alpha-(3,4-dimethoxy) phenylethyl)-methylamino] propyl) phthalimidine (AQ-A 39), a specific bradycardic agent. Arzneimittelforschung. 31(4):666–670 (1981).PubMedGoogle Scholar
  13. 13.
    W. Kobinger and C. Lillie. Falipamil (AQ-A 39) and UL-FS 49. Cardiovasc. Drug Rev. 6:35–43 (1988).CrossRefGoogle Scholar
  14. 14.
    R. G. Shanks. The clinical pharmacology of alinidine and its side-effects. Eur. Heart J. 8(Suppl L):83–90 (1987).PubMedGoogle Scholar
  15. 15.
    W. H. Frishman, C. J. Pepine, R. J. Weiss, and W. M. Baiker. Addition of zatebradine, a direct sinus node inhibitor, provides no greater exercise tolerance benefit in patients with angina taking extended-release nifedipine: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The Zatebradine Study Group. J. Am. Coll. Cardiol. 26(2):305–312 (1995).PubMedCrossRefGoogle Scholar
  16. 16.
    S. P. Glasser, D. D. Michie, U. Thadani, and W. M. Baiker. Effects of zatebradine (ULFS 49 CL), a sinus node inhibitor, on heart rate and exercise duration in chronic stable angina pectoris. Zatebradine Investigators. Am. J. Cardiol. 79(10):1401–1405 (1997).PubMedCrossRefGoogle Scholar
  17. 17.
    A. Granetzny, U. Schwanke, C. Schmitz, G. Arnold, D. Schafer, H. D. Schulte, E. Gams, and J. D. Schipke. Pharmacologic heart rate reduction: effect of a novel, specific bradycardic agent on the heart. Thorac. Cardiovasc. Surg. 46(2):63–69 (1998).PubMedCrossRefGoogle Scholar
  18. 18.
    V. P. Shah, K. K. Midha, and S. Dighe. Conference report. Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. Pharm. Res. 9:588–592 (1992).CrossRefGoogle Scholar
  19. 19.
    S. L. Beal and L. B. Sheiner. NONMEM Users Guide, NONMEM project group, University of Carlifornia, San Francisco, CA, 1992.Google Scholar
  20. 20.
    J. W. Mandema, D. Verotta, and L. B. Sheiner. Building population pharmacokinetic–pharmacodynamic models. I. Models for covariate effects. J. Pharmacokinet. Biopharm. 20(5):511–528 (1992).PubMedCrossRefGoogle Scholar
  21. 21.
    E. N. Jonsson and M. O. Karlsson. Xpose-an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput. Methods Programs Biomed. 58(1):51–64 (1999).PubMedCrossRefGoogle Scholar
  22. 22.
    P. O. Maitre, M. Buhrer, D. Thomson, and D. R. Stanski. A three-step approach combining Bayesian regression and NONMEM population analysis: application to midazolam. J. Pharmacokinet. Biopharm. 19(4):377–384 (1991).PubMedCrossRefGoogle Scholar
  23. 23.
    E. N. Jonsson and M. O. Karlsson. Automated covariate model building within NONMEM. Pharm. Res. 15(9):1463–1468 (1998).PubMedCrossRefGoogle Scholar
  24. 24.
    S. L. Beal and L. B. Sheiner. Estimating population kinetics. Crit. Rev. Biomed. Eng. 8(3):195–222 (1982).PubMedGoogle Scholar
  25. 25.
    S. L. Beal. Population pharmacokinetic data and parameter estimation based on their first two statistical moments. Drug Metab. Rev. 15(1–2):173–193 (1984).PubMedCrossRefGoogle Scholar
  26. 26.
    Center for Drug Evaluation and Research (C.D.E.R.). Population Pharmacokinetics, Guidance for Industry, Rockville, 1999.Google Scholar
  27. 27.
    L. B. Sheiner and S. L. Beal. Some suggestions for measuring predictive performance. J. Pharmacokinet. Biopharm. 9(4):503–512 (1981).PubMedCrossRefGoogle Scholar
  28. 28.
    Y. Yano, S. L. Beal, and L. B. Sheiner. Evaluating pharmacokinetic/pharmacodynamic models using the posterior predictive check. J. Pharmacokinet. Pharmacodyn. 28(2):171–192 (2001).PubMedCrossRefGoogle Scholar
  29. 29.
    M. O. Karlsson and L. B. Sheiner. The importance of modeling interoccasion variability in population pharmacokinetic analyses. J. Pharmacokinet. Biopharm. 21(6):735–750 (1993).PubMedCrossRefGoogle Scholar
  30. 30.
    H. Franke, C. A. Su, K. Schumacher, and M. Seiberling. Clinical pharmacology of two specific bradycardiac agents. Eur. Heart J. 8(Suppl L):91–98 (1987).PubMedGoogle Scholar
  31. 31.
    W. Roth, E. Bauer, G. Heinzel, P. J. Cornelissen, R. G. van Tol, J. H. Jonkman, and P. B. Zuiderwijk. Zatebradine: pharmacokinetics of a novel heart-rate-lowering agent after intravenous infusion and oral administration to healthy subjects. J. Pharm. Sci. 82(1):99–106 (1993).PubMedCrossRefGoogle Scholar
  32. 32.
    I. Ragueneau, C. Laveille, R. Jochemsen, G. Resplandy, C. Funck-Brentano, and P. Jaillon. Pharmacokinetic–pharmacodynamic modeling of the effects of ivabradine, a direct sinus node inhibitor, on heart rate in healthy volunteers. Clin. Pharmacol. Ther. 64(2):192–203 (1998).PubMedCrossRefGoogle Scholar
  33. 33.
    S. B. Duffull, S. Chabaud, P. Nony, C. Laveille, P. Girard, and L. Aarons. A pharmacokinetic simulation model for ivabradine in healthy volunteers. Eur. J. Pharm. Sci. 10(4):285–294 (2000).PubMedCrossRefGoogle Scholar
  34. 34.
    R. Savic, D. M. Jonker, T. Kerbusch, and M. O. Karlsson. Evaluation of a transit compartment model versus lag time model for describing drug absorption delay. 13th Population Approach Group Europe Meeting, Uppsala, Sweden, Abstract 513 (2004).Google Scholar
  35. 35.
    S. Vozeh, J. L. Steimer, M. Rowland, P. Morselli, F. Mentre, L. P. Balant, and L. Aarons. The use of population pharmacokinetics in drug development. Clin. Pharmacokinet. 30(2):81–93 (1996).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Gabriele Fliss
    • 1
  • Alexander Staab
    • 2
  • Christiane Tillmann
    • 2
  • Dirk Trommeshauser
    • 2
  • Hans G. Schaefer
    • 2
  • Charlotte Kloft
    • 1
    • 3
  1. 1.Department of Clinical Pharmacy, Institute of PharmacyFreie Universitaet BerlinBerlinGermany
  2. 2.Boehringer Ingelheim Pharma GmbH & Co. KGBiberach a.d.R.Germany
  3. 3.Department of Clinical Pharmacy, Faculty of PharmacyMartin-Luther-Universitaet Halle-WittenbergHalleGermany

Personalised recommendations