Skip to main content
SpringerLink
Log in

On the dose dependency of Cyclosporin a absorption and disposition in healthy volunteers

  • Published:
Journal of Pharmacokinetics and Biopharmaceutics Aims and scope Submit manuscript

Abstract

The pharmacokinetics of Cyclosporin A (CyA, SandimmuneR) was studied in 12 healthy male volunteers after oral dosing of 350 mg, 700 mg, and 1400 mg as a drinking solution. Blood samples were collected over 96 hr and analyzed by high pressure liquid chromatography. Concentration data were evaluated with model-independent and model-based linear pharmacokinetic concepts. Individual CyA concentration-time profiles in whole blood were well described by a two-compartment open model with zero-order absorption for all three doses. Comparison of pharmacokinetic parameters across doses indicates that both absorption and disposition are dose-dependent. Nonlinear disposition is suggested by the significant increase of the terminal half-life from 8.9±4.9hr to 11.9±4.9hr (mean±SD) after a 350 mg and a 1400 mg dose, respectively. Changes in the metabolic activity of the liver with concentration might be responsible for this phenomenon. In addition, the modeling approach indicated that bioavailability decreases with increasing dose. Moreover, the dependence of the rate of CyA absorption (zero-order rate constant) versus dose was well described by a hyperbola. The limited solubility of the drug in the gastrointestinal tract might be responsible for this behavior. The lag time (0.2–0.8 hr) was independent of dose. This value is similar to the time of gastric emptying in fasting volunteers. The duration of absorption for 11 of 12 subjects was in the range 2.5–3.5 hr over all doses and agrees well with the small intestine transit time. Some subjects showed a marked secondary peak at one or two doses, which could be adequately fitted by a model with two successive zero-order inputs. This double-peak behavior was ascribed to the influence of the food on gastric emptying. Dose dependency of disposition and absorption counterbalance each other in the usual dose range. This leads to an almost proportional increase of area under the blood CyA concentration-time profile with increasing dose.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. R. J. Ptachcinski, R. Venkataramanan, and G. J. Burckart. The clinical pharmacokinetics of cyclosporine.Clin. Pharmacokin. 11:107–132 (1986).

    Article  CAS  Google Scholar 

  2. R. J. Ptachcinski, R. Venkataramanan, G. J. Burckart, J. T. Rosenthal, R. J. Taylor, and T. R. Hakala. Dose-dependent absorption of cyclosporineDrug Intell. Clin. Pharm. 19:450 (1985).

    Google Scholar 

  3. B. D. Kahan. Individualization of cyclosporine therapy using pharmacokinetic and pharmacodynamic parameters. Transplantation40:457–476 (1985).

    Article  CAS  PubMed  Google Scholar 

  4. J. Grevel, E. Nüesch, E. Abisch, and K. Kutz. Pharmacokinetics of oral cyclosporin A in healthy subjects.Eur. J. Clin. Pharmacol. 31:211–216 (1986).

    Article  CAS  PubMed  Google Scholar 

  5. C. R. Abolin, H. F. Schran, D. W. Bitz, and S. Solar-Yohay.A Study of the Dose-Bioavailbility Relationship of Sandimmune Oral Solution in Normal Volunteers (Study No. 50), Sandoz Inc., East-Hanover, 1982.

    Google Scholar 

  6. D. Du Bois and E. F. Du Bois. A formula to estimate the approximate surface area if height and weight be known.Arch. Intern. Med. 17:863 (1916).

    Article  Google Scholar 

  7. H. T. Smith and W. T. Robinson. Semi-automated liquid chromatographic method for the determination of cyclosporine in plasma and blood using column switching.J. Chromatog. 305:353–362 (1984).

    Article  CAS  Google Scholar 

  8. R. J. Ptachcinski, R. Venkataramanan, G. J. Burckart, J. Gray, D. H. Van Thiel, A. Sanghvi, and J. T. Rosenthal. Cyclosporine kinetics in normal volunteers.J. Clin. Pharmacol. 27:243–248 (1987).

    Article  CAS  PubMed  Google Scholar 

  9. J. P. Reymond. In vitro in vivo Modelle zur Absorption von Cyclosporin A. Ph.D. dissertation, University of Basel, 1986.

  10. L. B. Sheiner. ELSFIT, a program for the extended least squares fit to individual pharmacokinetic data. A technical report of the Division of Clinical Pharmacology, University of California, 1980.

  11. D. Perrier and M. Mayersohn. Noncompartmental determination of the steady-state volume of distribution for any mode of administration.J. Pharm. Sci. 71:372–373 (1982).

    Article  CAS  PubMed  Google Scholar 

  12. P. R. Gwilt, M. C. Pankaskie, J. E. Thornburg, R. Zustiak, and D. R. Shoenthal. Pharmacokinetics of methylprylon following a single oral dose.J. Pharm. Sci. 74:1001–1003 (1985).

    Article  CAS  PubMed  Google Scholar 

  13. RS/1Version 12.00. BBN Research Systems, Cambridge, MA, 1984.

  14. E. M. Landaw and J. J. Distefano III. Multiexponential, multicompartmental, and noncompartmental modeling II. Data analysis and statistical considerations.Am. J. Physiol. 246:R665-R677 (1984).

    CAS  PubMed  Google Scholar 

  15. L. J. Lesko, J. Minor, D. Yocum, T. Emm, and J. H. Klippel. Pharmacokinetics of cyclosporine in patients with rheumatoid arthiritis.Clin. Pharmacol. Ther. 39:207 (1986).

    Google Scholar 

  16. S. Øie, T. W. Guentert, and T. N. Tozer. Effect of saturable binding on the pharmacokinetics of drugs: a simulation.J. Pharm. Pharmacol. 32:471–477 (1980).

    Article  PubMed  Google Scholar 

  17. K. Nussbaumer. Biopharmazeutische Untersuchungen mit Cyclosporin A: Bioanalytik und Pharmakokinetik. Ph.D. dissertation, University of Basel, Switzerland, 1984.

    Google Scholar 

  18. M. Rowland and T. Tozer.Clinical Pharmacokinetics, Lea and Febiger, Philadelphia, 1980, p. 45.

    Google Scholar 

  19. T. Beveridge. Pharmacokinetics and metabolism of Cyclosporin A. In D. J. G. White (ed.),Cyclosporin A, Elsevier Biomedical Press, Amsterdam, 1982, pp. 35–44.

    Google Scholar 

  20. R. J. Ptachcinski, R. Venkataraman, G. J. Burckart, S. Yang, and T. E. Starzl. Extraction ratio of cyclosporine in a liver transplant patient with organ rejection.J. Pharm. Sci. 74:901–902 (1985).

    Article  PubMed Central  PubMed  Google Scholar 

  21. W. M. Awni and R. J. Sawchuk. The pharmacokinetics of cyclosporine. I. single dose and constant rate infusion studies in the rabbit.Drug Metab. Dispos. 13:127–132 (1985).

    CAS  PubMed  Google Scholar 

  22. W. M. Awni and R. J. Sawchuck. The pharmacokinetics of cyclosporine. II. blood plasma distribution and binding studies.Drug Metab. Dispos. 13:133–138 (1985).

    CAS  PubMed  Google Scholar 

  23. K. Nooter, F. Schultz, and P. Sonneveld. Evidence for a possible dose-dependent pharmacokinetic of cyclosporin A in the rat.Res. Commun. Chem. Pathol. Pharmacol. 43:407–415 (1984).

    CAS  PubMed  Google Scholar 

  24. S. K. Gupta, B. Legg, L. R. Solomon, R. W. G. Johnson, and M. Rowland: Pharmacokinetics of cyclosporin: influence of rate of constant intravenous infusion in renal transplant patients.Br. J. Clin. Pharmacol. 24:519–526 (1987).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. C. T. Ueda, M. Lemaire, G. Gsell, P. Misslin, and K. Nussbaumer. Apparent dose-dependent oral absorption of cyclosporin A in rats.Biopharm. Drug Dispos. 5:141–151 (1984).

    Article  CAS  PubMed  Google Scholar 

  26. J. G. Wagner, A modern view of pharmacokinetics.J. Pharmacokin. Biopharm. 1:363–401 (1973).

    Article  CAS  Google Scholar 

  27. P. J. McNamara, W. A. Colburn, and M. Gibaldi. Absorption kinetics of hydroflumethiazide.J. Clin. Pharmacol. 18:190–193 (1978).

    Article  CAS  PubMed  Google Scholar 

  28. P. G. Welling, L. L. Lyons, B. S. R. Elliott, and G. L. Amidon. Pharmacokinetics of alcohol following single low doses to fasted and non fasted subjects.J. Clin. Pharmacol. 17:199–206 (1977).

    Article  CAS  PubMed  Google Scholar 

  29. L. R. Whitfield, P. N. Kaul, and M. L. Clark. Chloropromazine metabolism. IX pharmacokinetics of chloropromazine following oral administration in man.J. Pharmacokin. Biopharm. 6:187–196 (1978).

    Article  CAS  Google Scholar 

  30. R. M. J. Ings, J. R. Lawrence, A. McDonald, J. McEwan, A. W. Pidgen, and J. D. Robinson. Glibenclamide pharmacokinetics in healthy volunteers: Evidence for zero-order drug absorption.Proc. Br. Pharmacol. Soc.:264p–265p (1981).

  31. T. W. Guentert, N. H. G. Holford, P. E. Coates, R. A. Upton, and S. Riegelman. Quinidine pharmacokinetics in man: choice of a disposition model and absolute bioavailability studies.J. Pharmacokin. Biopharm. 7:315–330 (1979).

    Article  CAS  Google Scholar 

  32. M. Thibonnier, N. H. G. Holford, R. A. Upton, C. D. Blume, and R. L. Williams. Pharmacokinetic-pharmacodynamic analysis of unbound disopyramide directly measured in serial plasma samples in man.J. Pharmacokin. Biopharm. 12:559–573 (1984).

    Article  CAS  Google Scholar 

  33. E. Redalieu, K. K. H. Chan, V. Tipnis, S. B. Zak, T. G. Gilleran, W. E. Wagner Jr., and A. R. LeSher. Kinetics of hydrochorothiazide absorption in humans.J. Pharm. Sci. 74:765–767 (1985).

    Article  CAS  PubMed  Google Scholar 

  34. J. R. Malagelada, J. S. Robertson, M. L. Brown, M. Remington, J. A. Duenes, G. M. Thomforde, and P. W. Carryer. Intestinal transit of solid and liquid components of a meal in health.Gastroenterology 87:1255–1263 (1984).

    CAS  PubMed  Google Scholar 

  35. R. Wassef, Z. Cohen, S. Nordgren, and B. Langer. Cyclosporine absorption in intestinal transplantation.Transplantation 39:496–499 (1985).

    Article  CAS  PubMed  Google Scholar 

  36. R. Venkataramanan, T. E. Starzl, S. Yang, G. J. Burckart, R. J. Ptachcinski, B. W. Shaw, S. Iwatsuki, D. H. VanThiel, A. Sanghvi, and H. Seltman. Biliary excretion of cyclosporine in liver transplant patients.Transplant. Proc. 17(1):286–289 (1985).

    PubMed Central  PubMed  Google Scholar 

  37. J. Spenard, G. Sirois, and M. A. Gagnon. The second peak in the serum levels curve after oral administrtion of a slow-release quinidine dosage form: effect of food.Br. J. Clin. Pharmacol. 13:752–754 (1982).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. P. G. Welling. Influence of food and diet on gastrointestinal drug absorption: a review.J. Pharmacokin. Biopharm. 5:291–334 (1977).

    Article  CAS  Google Scholar 

  39. P. G. Welling. Interactions affecting drug absorption.Clin. Pharmacokin. 9:404–434 (1984).

    Article  CAS  Google Scholar 

  40. W. Andrews, S. Iwatsuki, and T. E. Starzl. Letter.Transplantation 39:338 (1985).

    Article  CAS  PubMed  Google Scholar 

  41. P. A. Keown, C. R. Stiller, M. Stawecki, J. McMichael, and W. Howson. Pharmacokinetics and interactions of ciclosporin In R. Schindler (ed.),Ciclosporin in Autoimmune Diseases, Springer Verlag, Berlin, 1985, pp. 39–42.

    Chapter  Google Scholar 

  42. A. J. Wood and M. Lemaire. Pharmacologic aspects of cyclosporine therapy: Pharmacokinetics.Transplant. Proc. 17(4, Suppl 1):27–32 (1985).

    CAS  PubMed  Google Scholar 

  43. R. J. Ptachcinski, R. Venkataramanan, J. T. Rosenthal, G. J. Burckart, R. J. Taylor, and T. R. Hakala. The effect of food on cyclosporine absorption.Transplantation 40:174–176 (1985).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Biopharmaceutical Department, Sandoz Ltd, CH-4002, Basel, Switzerland

    Jean-Philippe Reymond & Werner Niederberger

  2. Department of Biomathematics, INSERM U 194, 91 Boulevard de l'Hôpital, F-75634, Paris, France

    Jean-Louis Steimer

Authors
  1. Jean-Philippe Reymond
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jean-Louis Steimer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Werner Niederberger
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This work is part of the doctoral dissertation of Jean-Philippe Reymond.

Partly supported by “Contrat de prestation 84112” between INSERM and Sandoz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reymond, JP., Steimer, JL. & Niederberger, W. On the dose dependency of Cyclosporin a absorption and disposition in healthy volunteers. Journal of Pharmacokinetics and Biopharmaceutics 16, 331–353 (1988). https://doi.org/10.1007/BF01062550

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01062550

Key words

Search

Navigation