Skip to main content
SpringerLink
Log in

A Pharmacokinetic Study of Cyclosporin (Sandimmune®)

Factors Affecting the Usefulness of Trough Levels in Predicting Drug Exposure in Renal Transplant Patients

  • Clinical Pharmacokinetics
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Summary

In this study, we have investigated the absorption and elimination kinetics of cyclosporin (CsA) at once-daily and twice-daily (at 0800h and 2000h) dosage intervals from the 2 earlier dosage forms, Sandimmune® Oral Solution (OS) and Sandimmune® Soft Gel Capsules (SGC), in 11 stable renal transplant patients. Our objective was to illustrate and explain the factors that are responsible for the poor performance of trough levels in the prediction of CsA exposure and to show how these problems may be overcome in the future by the administration of a new dosage form of CSA, Sandimmune Neoral® (Neoral®). Predose trough levels for OS and SGC in the 0800- and 2000-hour intervals, and for SGC in the once-daily interval, were not significantly different. In the 0800-hour interval, the time to maximum drug concentration for the OS dosage form was significantly longer than for SGC. Analysis of the data from all patients showed no significant difference in dose-adjusted area under the concentration-time curve from zero to 12 hours (AUC0–12h) between 0800-hour and once-daily intervals; however, those results were affected by high intrasubject variability in absorption rate exhibited by a few individuals. Analysis of the data from 7 individuals with very uniform blood CsA concentration profiles revealed a significant dose-dependent effect on CsA absorption. Diurnal fluctuations in SGC absorption rate and extent had significant effects on postdose trough levels: in the 2000-hour interval, postdose trough concentration (Cmin12) was significantly higher than predose trough concentration (Cmin0). This change reflected both delays in absorption as well as increases in absorption extent. The assessment of the predictive potential of CsA trough levels from SGC 12- (0800-hour) and 24-hour (once-daily) intervals revealed poor correlations between: (1) dose vs AUC0–12h (r = 0.17) and AUC0–24h (r = 0.21), (2) dose vs pre- and postdose 12-hour trough concentrations (r < 0.2 in all cases), and (3) AUC0–12h vs predose (r = 0.16) and postdose (r = 0.49) 12-hour trough concentrations. Better correlations were observed with AUC0–24h vs 24-hour predose (r = 0.85) and postdose (r = 0.88) trough concentrations. The results in this study thus serve to illustrate the complexity underlying the use of predose trough concentrations to either predict the AUC, or calculate a dose, for a subsequent dosage interval.

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. Dossing M, Poulsen HE, Andreasen PB, et al. A simple method for determination of antipyrine clearance. Clin Pharmacol Ther 1982; 32: 392–6

    Article  PubMed  CAS  Google Scholar 

  2. Dossing M, Volund A, Poulsen HE. Optimal sampling times for minimum variance of clearance determination. Br J Clin Pharmacol 1983: 15: 231–5

    Article  PubMed  CAS  Google Scholar 

  3. Klompmaker IJ, Wierda JMKH, Sluiter WJ, et al. Pharmacokinetics of cyclosporine A after intravenous and oral administration in liver transplant patients measured with high performance liquid chromatography. Ther Drug Monit 1993; 15: 60–4

    Article  PubMed  CAS  Google Scholar 

  4. Kahan BD. Individualization of cyclosporine therapy using pharmacokinetic and pharmacodynamic parameters. Transplantation 1985; 40: 457–74

    Article  PubMed  CAS  Google Scholar 

  5. Grevel J. Significance of cyclosporine pharmacokinetics. Transplant Proc 1988; 20 Suppl. 2: 428–34

    PubMed  CAS  Google Scholar 

  6. Newburger J, Kahan BD. Cyclosporine pharmacokinetics in man. Transplant Proc 1983; 15: 2413

    Google Scholar 

  7. Yee GC, Kennedy MS, Storb R, et al. Effect of hepatic dysfunction on oral cyclosporine pharmacokinetics in marrow transplant patients. Blood 1984; 64: 1377

    Google Scholar 

  8. Gupta SK, Manfro RC, Tomlanovich SJ, et al. Effect of food on the pharmacokinetics of cyclosporine in healthy subjects following oral and intravenous administration. J Clin Pharmacol 1990; 30: 643–53

    PubMed  CAS  Google Scholar 

  9. Ptachcinski RJ, Venkataramanan R, Burckart GJ, et al. Dose-dependent absorption of cyclosporine. Drug Intell Clin Pharm 1985; 19: 450

    Google Scholar 

  10. Kahan BD, Ried M, Newburger J. Pharmacokinetics of cyclosporine in human renal transplantation. Transplant Proc 1983; 15: 446–53

    Google Scholar 

  11. Phillips TM, Karmi SA, Frantz SC, et al. Absorption profiles of renal allograft recipients receiving oral doses of cyclosporine: a pharmacokinetic study. Transplant Proc 1988: 20: 457–61

    PubMed  CAS  Google Scholar 

  12. Lindholm A, Henricsson S, Lind M, et al. Intraindividual variability in the relative systemic availability of cyclosporine after oral dosing. Eur J Clin Pharmacol 1988; 34: 461–4

    Article  PubMed  CAS  Google Scholar 

  13. Lindholm A, Welsh M, Alton C, et al. Demographic factors influencing cyclosporine pharmacokinetic parameters in patients with uremia: racial differences in bioavailability. Clin Pharmacol Ther 1992; 52: 359–71

    Article  PubMed  CAS  Google Scholar 

  14. Grevel J, Kutz K, Abisch E, et al. Evidence for zero-order absorption of cyclosporine A [abstract]. Br J Pharmacol 1986; 22: 220

    Google Scholar 

  15. Reymond JP, Steimer JL, Niederberger W. On the dose dependency of cyclosporine A absorption and disposition in healthy volunteers. J Pharmacokinet Biopharm 1988; 16: 331–53

    PubMed  CAS  Google Scholar 

  16. Lindholm A. Review: factors influencing the pharmacokinetics of cyclosporine in man. Ther Drug Monit 1991; 13: 465–77

    Article  PubMed  CAS  Google Scholar 

  17. Frey FJ, Horben FF, Frey BM. Trough levels and concentration time curves of cyclosporine in patients undergoing renal transplantation. Clin Pharmacol Ther 1988; 43: 55–62

    Article  PubMed  CAS  Google Scholar 

  18. Grevel J, Post BK, Kahan BD. Michaelis-Menten kinetics determine cyclosporine steady-state concentrations: a population analysis in kidney transplant patients. Clin Pharmacol Ther 1993: 53: 651–60

    Article  PubMed  CAS  Google Scholar 

  19. Nashan B, Bleck J, Wonigeit K, et al. Effect of the application form of cyclosporine on blood levels: comparison of oral solution and capsules. Transplant Proc 1988; 20[2]: 637–9

    PubMed  CAS  Google Scholar 

  20. Zehnder C, Beveridge T, Nuesch E, et al. Cyclosporine A capsules: bioavailability and clinical acceptance in renal transplant patients. Transplant Proc 1988; 20 Suppl. 2: 641–3

    PubMed  CAS  Google Scholar 

  21. Humbert H, Vernillet L, Cabiac MD, et al. Influence of different parameters for the monitoring of cyclosporine. Transplant Proc 1990; 22(3): 1210–5

    PubMed  CAS  Google Scholar 

  22. Reinberg A, Smolensky MH. Circadian changes of drug disposition in man. Clin Pharmacokinet 1982: 7: 401–20

    Article  PubMed  CAS  Google Scholar 

  23. Canafax D, Cipolle R, Hrushesky W, et al. The chrono-pharmacokinetics of cyclosporine and its metabolites in recipients of pancreas allografts. Transplant Proc 1988; 20 Suppl. 2: 471–7

    PubMed  CAS  Google Scholar 

  24. Cipolle R, Canafax D, Rabatin J, et al. Time-dependent disposition of cyclosporine after pancreas transplantation, and application of chronopharmacokinetics to improve immunosuppression. Pharmacotherapy 1988; 8: 47–51

    PubMed  CAS  Google Scholar 

  25. Sabate I, Grino JM, Castalao AM, et al. Diurnal variations of cyclosporine and metabolites in renal transplant patients. Transplant Proc 1990; 22(4): 1700–1

    PubMed  CAS  Google Scholar 

  26. Scheiner LB, Beal SL. Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 1981; 9: 503–12

    Google Scholar 

  27. Kovarik JM, Mueller EA, Van Bree JB, et al. Cyclosporine pharmacokinetics and variability from a microemulsion formulation — a multicenter investigation in kidney transplant patients. Transplantation 1994; 58: 658–63

    PubMed  CAS  Google Scholar 

  28. Levy G, Grant D. Potential for CsA-Neoral in organ transplantation. In: Kahan BD, editor. Cyclosporine, the ten-year experience. Norwalk Conn: Appleton & Lange, 1994: 2932–4

    Google Scholar 

  29. Kahan BD, Dunn J, Fitts C, et al. The Neoral formulation: improved correlation between cyclosporine trough levels and exposure in stable renal transplant patients. In: Kahan BD, editor. Cyclosporine, the ten-year experience. Norwalk Conn: Appleton & Lange, 1994: 2940–3

    Google Scholar 

  30. Mikhail G, Eadon H, Leaver N, et al. Use of Neoral in heart transplant recipients. In: Kahan BD, editor. Cyclosporine, the ten-year experience. Norwalk Conn: Appleton & Lange, 1994: 2985–7

    Google Scholar 

  31. Fiocchi F, Mam-Prin F, Gamba A, et al. Pharmacokinetic profile of cyclosporine in long-term heart transplanted patients treated with a new oral formulation. Transplant Proc 1994; 26(5): 2994–5

    PubMed  CAS  Google Scholar 

  32. Holt DW, Mueller EA, Kovarik JM, et al. The pharmacokinetics of Sandimmun Neoral: a new oral formulation of cyclosporine. In: Kahan BD, editor. Cyclosporine, the ten-year experience. Norwalk Conn: Appleton & Lange, 1994: 2935–9

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Immunology Laboratory, Division of Haematopathology, Department of Pathology, Vancouver Hospital and Health Sciences Centre, 910 West 10th Avenue, Vancouver, British Columbia, Canada, V5Z 1M9

    Dennis R. N. Primmett, Rebecca Wrishko & Paul A. Keown

  2. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada

    Dennis R. N. Primmett, Marc Levine & Rebecca Wrishko

  3. Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    Paul A. Keown

Authors
  1. Dennis R. N. Primmett
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marc Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rebecca Wrishko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paul A. Keown
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Primmett, D.R.N., Levine, M., Wrishko, R. et al. A Pharmacokinetic Study of Cyclosporin (Sandimmune®). Clin. Drug Invest. 13, 23–36 (1997). https://doi.org/10.2165/00044011-199713010-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00044011-199713010-00004

Keywords

Search

Navigation