Skip to main content
SpringerLink
Log in

Population pharmacokinetics and Bayesian estimation of cyclosporine in a Tunisian population of hematopoietic stem cell transplant recipient

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Therapeutic drug monitoring of cyclosporine minimizes the risk of toxicity and acute rejection after transplantation. Areas under the curve (AUCs) rather than trough concentration-based monitoring are recommended. Population pharmacokinetics (PopPK) modeling and Bayesian estimation seem to be the best way to predict cyclosporine disposition and dose requirements to achieve the therapeutic target in an individual patient because of the possibility of predicting cyclosporine AUC using only a few blood samples. Our objectives were to build a PopPk model for cyclosporine in a Tunisian population of HSCT patients and to develop a Bayesian method for the estimation of individual cyclosporine AUC.

Patients and methods

The PopPk of cyclosporine was studied using nonlinear mixed effects modeling (NONMEM) in 30 patients (index group) receiving cyclosporine on a twice-daily basis. Ten blood samples were collected after steady-state morning cyclosporine dose. Bayesian estimation of individual AUC was made on the basis of three blood concentration measurements in an independent group of 30 patients (test group).

Results

A two-compartment model with first-order absorption and a lag time provided the best fitting. The population mean estimate and interindividual variability from the final model for CL, Ka, Tlag, V1, V2, and Q were 25.4 L/h (CV = 38.72 %), 0.214 h−1(CV = 28.5 %), 0.382 h, 10.9 L (85.73 %), 496 L, and 5 L/h, respectively. Covariates had no discernible effects on cyclosporine pharmacokinetics in our population. Bayesian estimation provided an accurate estimation of AUC, although a bias was observed leading to slight underprediction of AUC (bias −1.03 %). A very satisfactory precision was observed (RMSE 12.07 %).

Conclusion

We report a PopPK model for cyclosporine in Tunisian HSCT patients. Bayesian estimation using only three concentrations provides good prediction of cyclosporine exposure. These tools allow us to routinely estimate cyclosporine AUC in a clinical setting.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Miller KB, Schenkein DP, Comenzo R, Erban JK, Fogaren T, Hirsch CA, Berkman E, Rabson A (1994) Adjusted-dose continuous-infusion cyclosporin A to prevent graft-versus-host disease following allogeneic bone marrow transplantation. Ann Hematol 68:15–20

    Article  PubMed  CAS  Google Scholar 

  2. Gondo H, Harada M, Taniguchi S, Akashi K, Hayashi S, Teshima T, Takamatsu Y, Eto T, Nagafuji K, Yamasaki K (1993) Cyclosporine combined with methylprednisolone or methotrexate in prophylaxis of moderate to severe acute graft-versus-host disease. Bone Marrow Transplant 2:437–441

    Google Scholar 

  3. Ptachcinski RJ, Venkataramanan R, Rosenthal JT, Burckart GJ, Taylor RJ, Hakaka TR (1985) The effect of food on cyclosporine absorption. Transplantation 40:174–176

    Article  PubMed  CAS  Google Scholar 

  4. Dunn CJ, Wagstaff AJ, Perry CM, Plosker GL, Goa KL (2001) Cyclosporin: an updated review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (neoral) 1 in organ transplantation. Drugs 61:1957–2016

    Article  PubMed  CAS  Google Scholar 

  5. Fahr A (1993) Cyclosporin clinical pharmacokinetics. Clin Pharmacokinet 24:472–495

    Article  PubMed  CAS  Google Scholar 

  6. Legg B, Rowland M (1987) Cyclosporin: measurement of fraction unbound in plasma. J Pharm Pharmacol 39:599–603

    Article  PubMed  CAS  Google Scholar 

  7. Trotter JF (1998) Drugs that interact with immunosuppressive agents. Semin Gastrointest Dis 9:147–153

    PubMed  CAS  Google Scholar 

  8. Zaghloul I, Ptachcinski RJ, Burckart GJ, Van Thiel D, Starzel TE, Venkataramanan R (1987) Blood protein binding of cyclosporine in transplant patients. J Clin Pharmacol 27:240–242

    PubMed  CAS  Google Scholar 

  9. Wang CP, Hartman NR, Venkataramanan R, Jardine I, Lin FT, Knapp JE, Starzl TE, Burckart GJ (1989) Isolation of 10 cyclosporine metabolites from human bile. Drug Metab Dispos 17:992–996

    Google Scholar 

  10. Venkataramanan R, Habucky K, Burckart GJ, Ptachcinski RJ (1989) Clinical pharmacokinetics in organ transplant patients. Clin Pharmacokinet 16:134–161

    Article  PubMed  CAS  Google Scholar 

  11. Pamala J, Ng J, Green KG, Rogosheske J, Brundage R (2003) Posttransplant day significantly influences pharmacokinetics of cyclosporine after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 9:304–11

    Article  Google Scholar 

  12. Jebabli N, Klouz A, Bahlous A, Gaies E, Trabelsi S, Lakhal M, Belkehia C (2007) Comparison of three methods for cyclosporine therapeutic monitoring. Transplant Proc 39:2557–2559

    Article  PubMed  CAS  Google Scholar 

  13. Beal SL, Sheiner LB, NONMEM Project Group C255 (1989) Nonlinear mixed effects modelling tool. University of California, San Francisco

  14. Yamaoka K, Nakagawa T, Uno T (1978) Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm 6:165–75

    PubMed  CAS  Google Scholar 

  15. Eljebari H, Ben Fradj N, Salouage I, Gaies E, Trabelsi S, Jebabli N, Lakhal M, Ben Othman T, Kouz A (2012) Estimation of abbreviated cyclosporine A area under the concentration-time curve in allogenic stem cell transplantation after oral administration. J Transplant. doi:10.1155/2012/342701

  16. Sheiner LB, Beal SL (1981) Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 9:503–12

    PubMed  CAS  Google Scholar 

  17. Sibbald C, Seto W, Taylor T, Saunders EF, Doyle J, Dupuis LL (2008) Determination of area under the whole blood concentration versus time curve after first intravenous cyclosporine dose in children undergoing hematopoietic stem cell transplant: limited sampling strategies. Ther Drug Monit 30:434–8

    PubMed  CAS  Google Scholar 

  18. Hadjibabaie M, Vazirian I, Iravani M, Moosavi SA, Alimoghaddam K, Ghavamzadeh A, Rezaee S (2011) Development and validation of limited sampling strategies for estimation of cyclosporine area under the concentration-time curve in hematopoietic stem cell transplant patients. Ther Drug Monit 33:673–80

    Article  PubMed  CAS  Google Scholar 

  19. McDonald GB, Shulman HM, Sullivan KM, Spencer GD (1986) Intestinal and hepatic complications of human bone marrow transplantation. Gastroenterology 90:770–784

    PubMed  CAS  Google Scholar 

  20. Schultz KR, Nevill TJ, Toze CL, Corrt T, Currie C, Strong DK, Keown PA (1998) The pharmacokinetics of oral cyclosporin A (Neoral) during the first month after bone marrow transplantation. Transplant Proc 30:1668–1670

    Article  PubMed  CAS  Google Scholar 

  21. Willemze AJ, Cremers SC, Schoemaker RC, Lankester AC, den Hartigh J, Burggraaf J, Vossen JM (2008) Ciclosporin kinetics in children after stem cell transplantation. Br J Clin Pharmacol 66:539–545

    Article  PubMed  CAS  Google Scholar 

  22. Wilhelm AJ, de Graaf P, Veldkamp AI, Janssen JJWM, Huijgens PC, Swart EL (2011) Population pharmacokinetics of ciclosporin in hematopoietic allogenic stem cell transplantation with emphasis on limited sampling strategy. Br J Clin Pharmacol 73(4):553–563. doi:10.1111/j.1365-2125.2011.04116.x

  23. Kim SH, Kim Kyung Im, Yun Hwi-yeol, Kang W, Yoon S-S, Shin WG, Lee Hye-suk, Jung Mi Oh (2010) Population pharmacokinetics of cyclosporine after hematopoietic stem cell transplantation in leukemic patients. Kor J Clin Pharm 20:9–16

    Google Scholar 

  24. Jacobson P, Ng J, Green KG, Rogosheske J, Brundage R (2003) Posttransplant day significantly influences pharmacokinetics of cyclosporine after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 9(5):304–311

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratoire de Pharmacologie Clinique, Centre National de Pharmacovigilance, 9 Avenue Dr. Zouheïr Essafi, 1006, Tunis, Tunisia

    Hanene Eljebari, Emna Gaies, Nadia Ben Fradj, Nadia Jebabli, Issam Salouage, Sameh Trabelsi, Mohamed Lakhal & Anis Klouz

  2. Faculté de Médecine, Tunis, Tunisia

    Emna Gaies, Nadia Ben Fradj, Nadia Jebabli, Issam Salouage, Sameh Trabelsi, Mohamed Lakhal & Anis Klouz

Authors
  1. Hanene Eljebari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emna Gaies
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nadia Ben Fradj
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nadia Jebabli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Issam Salouage
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sameh Trabelsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mohamed Lakhal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anis Klouz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hanene Eljebari.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eljebari, H., Gaies, E., Fradj, N.B. et al. Population pharmacokinetics and Bayesian estimation of cyclosporine in a Tunisian population of hematopoietic stem cell transplant recipient. Eur J Clin Pharmacol 68, 1517–1524 (2012). https://doi.org/10.1007/s00228-012-1275-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-012-1275-9

Keywords

Search

Navigation