Skip to main content
SpringerLink
Log in

Population Pharmacokinetics of Mycophenolic Acid

A Comparison between Enteric-Coated Mycophenolate Sodium and Mycophenolate Mofetil in Renal Transplant Recipients

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Objective: The pharmacokinetics of mycophenolic acid (MPA) were compared in renal transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS).

Methods: MPA concentration-time profiles were included from EC-MPS- (n = 208) and MMF-treated (n = 184) patients 4–257 months after renal transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling (NONMEM®). A two-compartment model with first-order absorption and elimination was used to describe the data.

Results: No differences were detected in MPA clearance, intercompartmental clearance, or the central or peripheral volume of distribution. Respective values and interindividual variability (IIV) were 16 L/h (39%), 22 L/h (78%), 40 L (100%) and 518 L (490%). EC-MPS was absorbed more slowly than MMF with respective absorption rate constant values of 3.0 h−1 and 4.1 h−1 (p < 0.001) [IIV 187%]. A mixture model was used for the change-point parameter lag-time (tlag) in order to describe IIV in this parameter adequately for EC-MPS. Following the morning dose of EC-MPS, the tlag values were 0.95, 1.88 and 4.83 h for 51%, 32% and 17% of the population (IIV 8%), respectively. The morning tlag following EC-MPS administration was significantly different from both the tlag following MMF administration (0.30 h; p < 0.001 [IIV 11%]) and the tlag following the evening dose of EC-MPS (9.04 h; p < 0.001 [IIV 40%]). Post hoc analysis showed that the tlag was longer and more variable following EC-MPS administration (morning median 2.0 h [0.9–5.5 h], evening median 8.9 h [5.4–12.3 h]) than following MMF administration (median 0.30 h [0.26–0.34 h]; p < 0.001). The morning MPA predose concentrations were higher and more variable following EC-MPS administration than following MMF administration, with respective values of 2.6 mg/L (0.4–24.4 mg/L) and 1.6 mg/L (0.2–7.6 mg/L). The correlation between predose concentrations and the area under the plasma concentration-time curve (AUC) was lower in EC-MPS-treated patients (r2 = 0.02) than in MMF-treated patients (r2 = 0.48).

Conclusion: Absorption of MPA was delayed and also slower following EC-MPS administration than following MMF administration. Furthermore, the tlag varied more in EC-MPS-treated patients. MPA predose concentrations were poorly correlated with the MPA AUC in both MMF- and EC-MPS-treated patients.

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

Table I
Table II
Fig. 1
Fig. 2
Table III
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References:

  1. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection: European Mycophenolate Mofetil Cooperative Study Group. Lancet 1995; 345(8961): 1321–5

    Google Scholar 

  2. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients: US Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1995; 60(3): 225–32

    Article  PubMed  CAS  Google Scholar 

  3. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation: the Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation 1996; 61(7): 1029–37

    Article  Google Scholar 

  4. Allison AC, Eugui EM. Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). Clin Transplant 1996; 10 (1 Pt 2): 77–84

    PubMed  CAS  Google Scholar 

  5. Budde K, Curtis J, Knoll G, et al. Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1-year study. Am J Transplant 2003; 4(2): 237–43

    Article  Google Scholar 

  6. Salvadori M, Holzer H, de Mattos A, et al. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2003; 4(2): 231–6

    Article  Google Scholar 

  7. Arns W, Breuer S, Choudhury S, et al. Enteric-coated mycophenolate sodium delivers bioequivalent MPA exposure compared with mycophenolate mofetil. Clin Transplant 2005; 19(2): 199–206

    Article  PubMed  Google Scholar 

  8. Budde K, Bauer S, Hambach P, et al. Pharmacokinetic and pharmacodynamic comparison of enteric-coated mycophenolate sodium and mycophenolate mofetil in maintenance renal transplant patients. Am J Transplant 2007; 7(4): 888–98

    Article  PubMed  CAS  Google Scholar 

  9. Budde K, Glander P, Kramer BK, et al. Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in maintenance renal transplant recipients receiving tacrolimus: clinical, pharmacokinetic, and pharmacodynamic outcomes. Transplantation 2007; 83(4): 417–24

    Article  PubMed  Google Scholar 

  10. Hale MD, Nicholls AJ, Bullingham RE, et al. The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplantation. Clin Pharmacol Ther 1998; 64(6): 672–83

    Article  PubMed  CAS  Google Scholar 

  11. Shaw LM, Holt DW, Oellerich M, et al. Current issues in therapeutic drug monitoring of mycophenolic acid: report of a roundtable discussion. Ther Drug Monit 2001; 23(4): 305–15

    Article  PubMed  CAS  Google Scholar 

  12. Le Meur Y, Buchler M, Thierry A, et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant 2007; 7(11): 2496–503

    Article  PubMed  Google Scholar 

  13. Tedesco-Silva H, Bastien MC, Choi L, et al. Mycophenolic acid metabolite profile in renal transplant patients receiving enteric-coated mycophenolate sodium or mycophenolate mofetil. Transplant Proc 2005; 37(2): 852–5

    Article  PubMed  CAS  Google Scholar 

  14. Pescovitz MD, Guasch A, Gaston R, et al. Equivalent pharmacokinetics of mycophenolate mofetil in African-American and Caucasian male and female stable renal allograft recipients. Am J Transplant 2003; 3(12): 1581–6

    Article  PubMed  CAS  Google Scholar 

  15. Cattaneo D, Cortinovis M, Baldelli S, et al. Pharmacokinetics of mycophenolate sodium and comparison with the mofetil formulation in stable kidney transplant recipients. Clin J Am Soc Nephrol 2007; 2(6): 1147–55

    Article  PubMed  CAS  Google Scholar 

  16. van Gelder T, Hilbrands LB, Vanrenterghem Y, et al. A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation. Transplantation 1999; 68(2): 261–6

    Article  PubMed  Google Scholar 

  17. Budde K, Glander P, Schuhmann R, et al. Conversion from cyclosporine to everolimus leads to better renal function and profound changes in everolimus pharmacokinetics [abstract]. Am J Transplant 2006; 6(S2): 999

    Google Scholar 

  18. Arns W, Glander P, Schuhmann R, et al. Conversion from tacrolimus to everolimus does not influence the pharmacokinetics but increases pharmacodynamic response of mycophenolate sodium in renal transplant patients [abstract]. Am J Transplant 2006; 6(S2): 488

    Google Scholar 

  19. Frame B, Miller R, Lalonde RL. Evaluation of mixture modeling with count data using NONMEM. J Pharmacokinet Pharmacodyn 2003; 30(3): 167–83

    Article  PubMed  CAS  Google Scholar 

  20. Lesaffre E, Rizopoulos D, Tsonaka R. The logistic transform for bounded outcome scores. Biostatistics (Oxford) 2007; 8(1): 72–85

    Article  Google Scholar 

  21. Jonsson EN, Karlsson MO. Xpose: an S-PLUS based population pharmacokinetic/ pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 1999; 58(1): 51–64

    Article  PubMed  CAS  Google Scholar 

  22. Ette EI, Williams PJ, Kim YH, et al. Model appropriateness and population pharmacokinetic modeling. J Clin Pharmacol 2003; 43(6): 610–23

    PubMed  CAS  Google Scholar 

  23. Jadhav PR, Gobburu JV. A new equivalence based metric for predictive check to qualify mixed-effects models. AAPS J 2005; 7(3): E523–31

    Article  PubMed  Google Scholar 

  24. Piotrovskii VK. The use of Weibull distribution to describe the in vivo absorption kinetics. J Pharmacokinet Biopharm 1987; 15(6): 681–6

    Article  PubMed  CAS  Google Scholar 

  25. Rietbrock S, Merz PG, Fuhr U, et al. Absorption behavior of sulpiride described using Weibull functions. Int J Clin Pharmacol Ther 1995; 33(5): 299–303

    PubMed  CAS  Google Scholar 

  26. Savic RM, Jonker DM, Kerbusch T, et al. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn 2007; 34(5): 711–26

    Article  PubMed  CAS  Google Scholar 

  27. Osterberg O, Savic RM, Karlsson MO, et al. Pharmacokinetics of desmopressin administrated as an oral lyophilisate dosage form in children with primary nocturnal enuresis and healthy adults. J Clin Pharmacol 2006; 46(10): 1204–11

    Article  PubMed  Google Scholar 

  28. Cremers S, Schoemaker R, Scholten E, et al. Characterizing the role of enterohepatic recycling in the interactions between mycophenolate mofetil and calcineurin inhibitors in renal transplant patients by pharmacokinetic modelling. Br J Clin Pharmacol 2005; 60(3): 249–56

    Article  PubMed  CAS  Google Scholar 

  29. Shum B, Duffull SB, Taylor PJ, et al. Population pharmacokinetic analysis of mycophenolic acid in renal transplant recipients following oral administration of mycophenolate mofetil. Br J Clin Pharmacol 2003; 56(2): 188–97

    Article  PubMed  CAS  Google Scholar 

  30. van Hest RM, Mathot RA, Pescovitz MD, et al. Explaining variability in mycophenolic acid exposure to optimize mycophenolate mofetil dosing: a population pharmacokinetic meta-analysis of mycophenolic acid in renal transplant recipients. J Am Soc Nephrol 2006; 17(3): 871–80

    Article  PubMed  Google Scholar 

  31. van Hest RM, van Gelder T, Vulto AG, et al. Population pharmacokinetics of mycophenolic acid in renal transplant recipients. Clin Pharmacokinet 2005; 44(10): 1083–96

    Article  PubMed  Google Scholar 

  32. Premaud A, Debord J, Rousseau A, et al. A double absorption-phase model adequately describes mycophenolic acid plasma profiles in de novo renal transplant recipients given oral mycophenolate mofetil. Clin Pharmacokinet 2005; 44(8): 837–47

    Article  PubMed  CAS  Google Scholar 

  33. Le Guellec C, Bourgoin H, Buchler M, et al. Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in stable renal transplant patients. Clin Pharmacokinet 2004; 43(4): 253–66

    Article  PubMed  Google Scholar 

  34. Goo RH, Moore JG, Greenberg E, et al. Circadian variation in gastric emptying of meals in humans. Gastroenterology 1987; 93(3): 515–8

    PubMed  CAS  Google Scholar 

  35. Satoh S, Tada H, Murakami M, et al. Circadian pharmacokinetics of mycophenolic acid and implication of genetic polymorphisms for early clinical events in renal transplant recipients. Transplantation 2006; 82(4): 486–93

    Article  PubMed  CAS  Google Scholar 

  36. Kagaya H, Inoue K, Miura M, et al. Influence of UGT1A8 and UGT2B7 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol 2007; 63(3): 279–88

    Article  PubMed  CAS  Google Scholar 

  37. Hesselink DA, van Hest RM, Mathot RA, et al. Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2. Am J Transplant 2005; 5(5): 987–94

    Article  PubMed  CAS  Google Scholar 

  38. Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 1998; 34(6): 429–55

    Article  PubMed  CAS  Google Scholar 

  39. Nowak I, Shaw LM. Mycophenolic acid binding to human serum albumin: characterization and relation to pharmacodynamics. Clin Chem 1995; 41(7): 1011–7

    PubMed  CAS  Google Scholar 

  40. Budde K, Tedesco-Silva H, Pestana JM, et al. Enteric-coated mycophenolate sodium provides higher mycophenolic acid predose levels compared with mycophenolate mofetil: implications for therapeutic drug monitoring. Ther Drug Monit 2007; 29(3): 381–4

    Article  PubMed  CAS  Google Scholar 

  41. van Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006; 28(2): 145–54

    Article  PubMed  Google Scholar 

  42. de Winter BC, Mathot RA, van Hest RM, et al. Therapeutic drug monitoring of mycophenolic acid: does it improve patient outcome? Expert Opin Drug Metab Toxicol 2007; 3(2): 251–61

    Article  PubMed  Google Scholar 

  43. Premaud A, Le Meur Y, Debord J, et al. Maximum a posteriori Bayesian estimation of mycophenolic acid pharmacokinetics in renal transplant recipients at different postgrafting periods. Ther Drug Monit 2005; 27(3): 354–61

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

No sources of funding were used to assist in the preparation of this study. Dr Teun van Gelder has received financial support for research, and lecture and consultancy fees from Roche Pharma and Novartis. Dr Dario Cattaneo has received lecture fees from Roche Pharma and a travel grant for attending a conference. Dr Helio Tedesco-Silva has received consultancy fees and grants from Roche Pharma and Novartis to design, conduct, analyse and review data obtained from clinical trials. Dr Luuk Hilbrands has received a grant from Roche Pharma for performing a clinical trial. Drs Mark Pescovitz and Klemens Budde have received honoraria, consultancy fees and research grants from Roche Pharma and Novartis. The other authors have no conflicts of interest that are directly relevant to the content of this study.

Author information

Authors and Affiliations

  1. Department of Hospital Pharmacy, Erasmus University Medical Center, ’s-Gravendijkwal 230, Rotterdam, 3015CE, The Netherlands

    Brenda C. M. de Winter, Teun van Gelder, Reinier M. van Hest & Ron A. A. Mathot

  2. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

    Teun van Gelder

  3. Department of Internal Medicine - Nephrology, Universitätsklinikum Charité Campus Mitte, Humboldt University, Berlin, Germany

    Petra Glander & Klemens Budde

  4. Center for Research on Organ Transplantation, Mario Negri Institute for Pharmacological Research, Bergamo, Italy

    Dario Cattaneo

  5. Hospital do Rim e Hipertensao, Universidade Federal de Sao Paulo, Sao Paulo, Brazil

    Helio Tedesco-Silva

  6. Department of Nephrology, Wilhelminenspital, Vienna, Austria

    Irmgard Neumann

  7. Department of Nephrology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Luuk Hilbrands

  8. Department of Surgery, Indiana University Medical Center, Indianapolis, Indiana, USA

    Mark D. Pescovitz

  9. Department of Microbiology/Immunology, Indiana University Medical Center, Indianapolis, Indiana, USA

    Mark D. Pescovitz

Authors
  1. Brenda C. M. de Winter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Teun van Gelder
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Petra Glander
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dario Cattaneo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Helio Tedesco-Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Irmgard Neumann
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Luuk Hilbrands
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Reinier M. van Hest
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mark D. Pescovitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Klemens Budde
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ron A. A. Mathot
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brenda C. M. de Winter.

Rights and permissions

Reprints and permissions

About this article

Cite this article

de Winter, B.C.M., van Gelder, T., Glander, P. et al. Population Pharmacokinetics of Mycophenolic Acid. Clin Pharmacokinet 47, 827–838 (2008). https://doi.org/10.2165/0003088-200847120-00007

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/0003088-200847120-00007

Keywords

Search

Navigation