Skip to main content
SpringerLink
Log in

Population Pharmacokinetics of Mycophenolic Acid Co-Administered with Tacrolimus in Corticosteroid-Free Adult Kidney Transplant Patients

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

Abstract

Background and Objective

Mycophenolic acid is commonly prescribed to adult kidney transplant recipients. Mycophenolic acid is extensively metabolized to mycophenolic acid-glucuronide (major metabolite) and mycophenolic acid-acyl-glucuronide (minor metabolite). We hypothesized that (1) adult kidney transplant patients on corticosteroid-free regimens exhibit unique mycophenolic acid population pharmacokinetics compared with patients receiving corticosteroid-based therapy, and (2) mycophenolic acid clearance is directly dependent on glucuronide metabolite formation.

Methods

Non-linear mixed-effects modeling was conducted with MonolixSuite-2018R1 (n = 27). Optimal pharmacokinetic models were selected based on objective function values, standard errors, and biological plausibility.

Results

Clinical demographic data were sex (female, 16), age (47 ± 13 years, mean ± standard deviation), weight (70 ± 16 kg), height (165 ± 9 cm), albumin (43 ± 4 g/L), serum creatinine (102 ± 27 µmol/L), estimated glomerular filtration rate (61 ± 16 mL/min/1.73 m2), mycophenolic acid dosage (1.4 ± 0.5 g/day, as mycophenolate mofetil), and tacrolimus dosage (5 ± 3 mg/day, immediate release). The population pharmacokinetics of mycophenolic acid can be described by a two-compartment first-order absorption with lag time, and a linear elimination structural model. The apparent oral clearance estimate in the final model (population mean, relative standard error) was 2.87 L/h, 42.3%, which is lower than that reported for similar patients on corticosteroid-based regimens (11.9–26.3 L/h). Other pharmacokinetic parameters were comparable to historical data obtained in corticosteroid-based patients. Both mycophenolic acid-acyl-glucuronide trough concentration and the area under the concentration–time curve ratio were significant covariates that reduced mycophenolic acid apparent oral clearance from 16.5 (base model) to 2.87 L/h. The model was evaluated based on bootstrapping, visual predictive checks, and diagnostic plots.

Conclusions

Our novel findings suggest the potential need to reduce mycophenolic acid dosage in subjects on corticosteroid-free regimens. Corticosteroid-free subjects may also be more sensitive to drug/gene interactions.

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

Similar content being viewed by others

References

  1. Kiang TKL, Ensom MHH. Population pharmacokinetics of mycophenolic acid: an update. Clin Pharmacokinet. 2018;57(5):547–58.

    CAS  PubMed  Google Scholar 

  2. Kiang TKL, Ensom MHH. Anti-rejection drugs. In: Murphy J, editor. Clinical pharmacokinetics. Bethesda: American Society of Health-System Pharmacists; 2017. pp. 205–20.

    Google Scholar 

  3. Kiang TKL, Ensom MH. Immunosuppressants. In: Beringer P, editor. Basic clinical pharmacokinetics. Philadelphia: Wolters Kluwer; 2017. pp. 320–58.

    Google Scholar 

  4. Kiang TKL, Ensom MHH. Therapeutic drug monitoring of mycophenolate in adult solid organ transplant patients: an update. Expert Opin Drug Metab Toxicol. 2016;12(5):545–53.

    CAS  PubMed  Google Scholar 

  5. Staatz CE, Tett SE. Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update. Arch Toxicol. 2014;88(7):1351–89.

    CAS  PubMed  Google Scholar 

  6. Kiang TKL, Partovi N, Shapiro RJ, Berman JM, Collier AC, Ensom MHH. Regression and genomic analyses on the association between mycophenolic acid exposure and absolute neutrophil count in steroid-free, de novo kidney transplant recipients. Clin Drug Investig. 2018;38(11):1011–22.

    CAS  PubMed  Google Scholar 

  7. Vincenti F, Schena FP, Paraskevas S, Hauser IA, Walker RG, Grinyo J, FREEDOM Study Group. A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients. Am J Transplant. 2008;8(2):307–16.

    CAS  PubMed  Google Scholar 

  8. Lemieux I, Houde I, Pascot A, Lachance JG, Noel R, Radeau T, et al. Effects of prednisone withdrawal on the new metabolic triad in cyclosporine-treated kidney transplant patients. Kidney Int. 2002;62(5):1839–47.

    CAS  PubMed  Google Scholar 

  9. Andrade-Sierra J, Rojas-Campos E, Cardona-Munoz E, Evangelista-Carrillo LA, Puentes-Camacho A, Lugo-Lopez O, et al. Early steroid withdrawal in a renal transplant cohort treated with tacrolimus, mycophenolate mofetil and basiliximab. Nefrologia. 2014;34(2):216–22.

    PubMed  Google Scholar 

  10. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet. 2007;46(1):13–8.

    CAS  PubMed  Google Scholar 

  11. Soars MG, Petullo DM, Eckstein JA, Kasper SC, Wrighton SA. An assessment of UDP-glucuronosyltransferase induction using primary human hepatocytes. Drug Metab Dispos. 2004;32(1):140–8.

    CAS  PubMed  Google Scholar 

  12. Qadri I, Hu LJ, Iwahashi M, Al-Zuabi S, Quattrochi LC, Simon FR. Interaction of hepatocyte nuclear factors in transcriptional regulation of tissue specific hormonal expression of human multidrug resistance-associated protein 2 (abcc2). Toxicol Appl Pharmacol. 2009;234(3):281–92.

    CAS  PubMed  Google Scholar 

  13. Cattaneo D, Perico N, Gaspari F, Gotti E, Remuzzi G. Glucocorticoids interfere with mycophenolate mofetil bioavailability in kidney transplantation. Kidney Int. 2002;62(3):1060–7.

    CAS  PubMed  Google Scholar 

  14. Greanya ED, Poulin E, Partovi N, Shapiro RJ, Al-Khatib M, Ensom MH. Pharmacokinetics of tacrolimus and mycophenolate mofetil in renal transplant recipients on a corticosteroid-free regimen. Am J Health Syst Pharm. 2012;69(2):134–42.

    CAS  PubMed  Google Scholar 

  15. Sherwin CM, Fukuda T, Brunner HI, Goebel J, Vinks AA. The evolution of population pharmacokinetic models to describe the enterohepatic recycling of mycophenolic acid in solid organ transplantation and autoimmune disease. Clin Pharmacokinet. 2011;50(1):1–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Staatz CE, Tett SE. Maximum a posteriori Bayesian estimation of mycophenolic acid area under the concentration-time curve: is this clinically useful for dosage prediction yet? Clin Pharmacokinet. 2011;50(12):759–72.

    CAS  PubMed  Google Scholar 

  17. Dong M, Fukuda T, Vinks AA. Optimization of mycophenolic acid therapy using clinical pharmacometrics. Drug Metab Pharmacokinet. 2014;29(1):4–11.

    CAS  PubMed  Google Scholar 

  18. Yu ZC, Zhou PJ, Wang XH, Francoise B, Xu D, Zhang WX, et al. Population pharmacokinetics and Bayesian estimation of mycophenolic acid concentrations in Chinese adult renal transplant recipients. Acta Pharmacol Sin. 2017;38(11):1566–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Colom H, Andreu F, van Gelder T, Hesselink DA, de Winter BCM, Bestard O, et al. Prediction of free from total mycophenolic acid concentrations in stable renal transplant patients: a population-based approach. Clin Pharmacokinet. 2018;57(7):877–93.

    CAS  PubMed  Google Scholar 

  20. Chen B, Shao K, An HM, Shi HQ, Lu JQ, Zhai XH, et al. Population pharmacokinetics and bayesian estimation of mycophenolic acid exposure in Chinese renal allograft recipients after administration of EC-MPS. J Clin Pharmacol. 2019;59(4):578–89.

    CAS  PubMed  Google Scholar 

  21. Yau WP, Vathsala A, Lou HX, Zhou S, Chan E. Mechanism-based enterohepatic circulation model of mycophenolic acid and its glucuronide metabolite: assessment of impact of cyclosporine dose in Asian renal transplant patients. J Clin Pharmacol. 2009;49(6):684–99.

    CAS  PubMed  Google Scholar 

  22. de Winter BC, van Gelder T, Sombogaard F, Shaw LM, van Hest RM, Mathot RA. Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients. J Pharmacokinet Pharmacodyn. 2009;36(6):541–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Cremers S, Schoemaker R, Scholten E, den Hartigh J, Konig-Quartel J, van Kan 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Musuamba FT, Rousseau A, Bosmans JL, Senessael JJ, Cumps J, Marquet P, et al. Limited sampling models and Bayesian estimation for mycophenolic acid area under the curve prediction in stable renal transplant patients co-medicated with ciclosporin or sirolimus. Clin Pharmacokinet. 2009;48(11):745–58.

    CAS  PubMed  Google Scholar 

  25. Sam WJ, Akhlaghi F, Rosenbaum SE. Population pharmacokinetics of mycophenolic acid and its 2 glucuronidated metabolites in kidney transplant recipients. J Clin Pharmacol. 2009;49(2):185–95.

    CAS  PubMed  Google Scholar 

  26. Colom H, Lloberas N, Andreu F, Caldes A, Torras J, Oppenheimer F, et al. Pharmacokinetic modeling of enterohepatic circulation of mycophenolic acid in renal transplant recipients. Kidney Int. 2014;85(6):1434–43.

    CAS  PubMed  Google Scholar 

  27. de Winter BC, Mathot RA, Sombogaard F, Vulto AG, van Gelder T. Nonlinear relationship between mycophenolate mofetil dose and mycophenolic acid exposure: implications for therapeutic drug monitoring. Clin J Am Soc Nephrol. 2011;6(3):656–63.

    PubMed  PubMed Central  Google Scholar 

  28. de Winter BC, Mathot RA, Sombogaard F, Neumann I, van Hest RM, Doorduijn JK, et al. Differences in clearance of mycophenolic acid among renal transplant recipients, hematopoietic stem cell transplant recipients, and patients with autoimmune disease. Ther Drug Monit. 2010;32(5):606–14.

    PubMed  Google Scholar 

  29. de Winter BC, Monchaud C, Premaud A, Pison C, Kessler R, Reynaud-Gaubert M, et al. Bayesian estimation of mycophenolate mofetil in lung transplantation, using a population pharmacokinetic model developed in kidney and lung transplant recipients. Clin Pharmacokinet. 2012;51(1):29–39.

    PubMed  Google Scholar 

  30. de Winter BC, van Gelder T, Glander P, Cattaneo D, Tedesco-Silva H, Neumann I, et al. Population pharmacokinetics of mycophenolic acid: a comparison between enteric-coated mycophenolate sodium and mycophenolate mofetil in renal transplant recipients. Clin Pharmacokinet. 2008;47(12):827–38.

    PubMed  Google Scholar 

  31. Staatz CE, Duffull SB, Kiberd B, Fraser AD, Tett SE. Population pharmacokinetics of mycophenolic acid during the first week after renal transplantation. Eur J Clin Pharmacol. 2005;61(7):507–16.

    CAS  PubMed  Google Scholar 

  32. Velickovic-Radovanovic RM, Jankovic SM, Milovanovic JR, Catic-Dordevic AK, Spasic AA, Stefanovic NZ, et al. Variability of mycophenolic acid elimination in the renal transplant recipients: population pharmacokinetic approach. Ren Fail. 2015;37(4):652–8.

    CAS  PubMed  Google Scholar 

  33. Shum B, Duffull SB, Taylor PJ, Tett SE. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Musuamba FT, Mourad M, Haufroid V, Demeyer M, Capron A, Delattre IK, et al. A simultaneous d-optimal designed study for population pharmacokinetic analyses of mycophenolic acid and tacrolimus early after renal transplantation. J Clin Pharmacol. 2012;52(12):1833–43.

    CAS  PubMed  Google Scholar 

  35. Lamba M, Tafti B, Melcher M, Chan G, Krishnaswami S, Busque S. Population pharmacokinetic analysis of mycophenolic acid coadministered with either tasocitinib (CP-690,550) or tacrolimus in adult renal allograft recipients. Ther Drug Monit. 2010;32(6):778–81.

    CAS  PubMed  Google Scholar 

  36. Guillet BA, Simon NS, Purgus R, Botta C, Morange S, Berland Y, et al. Population pharmacokinetics analysis of mycophenolic acid in adult kidney transplant patients with chronic graft dysfunction. Ther Drug Monit. 2010;32(4):427–32.

    CAS  PubMed  Google Scholar 

  37. Han N, Yun HY, Kim IW, Oh YJ, Kim YS, Oh JM. Population pharmacogenetic pharmacokinetic modeling for flip-flop phenomenon of enteric-coated mycophenolate sodium in kidney transplant recipients. Eur J Clin Pharmacol. 2014;70(10):1211–9.

    CAS  PubMed  Google Scholar 

  38. Funaki T. Enterohepatic circulation model for population pharmacokinetic analysis. J Pharm Pharmacol. 1999;51(10):1143–8.

    CAS  PubMed  Google Scholar 

  39. van Hest RM, Mathot RA, Pescovitz MD, Gordon R, Mamelok RD, van Gelder T. 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.

    PubMed  Google Scholar 

  40. van Hest RM, van Gelder T, Bouw R, Goggin T, Gordon R, Mamelok RD, et al. Time-dependent clearance of mycophenolic acid in renal transplant recipients. Br J Clin Pharmacol. 2007;63(6):741–52.

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  42. Le Guellec C, Buchler M, Giraudeau B, Le Meur Y, Gakoue JE, Lebranchu Y, et al. Simultaneous estimation of cyclosporin and mycophenolic acid areas under the curve in stable renal transplant patients using a limited sampling strategy. Eur J Clin Pharmacol. 2002;57(11):805–11.

    PubMed  Google Scholar 

  43. Ting LS, Partovi N, Levy RD, Riggs KW, Ensom MH. Pharmacokinetics of mycophenolic acid and its phenolic-glucuronide and ACYl glucuronide metabolites in stable thoracic transplant recipients. Ther Drug Monit. 2008;30(3):282–91.

    CAS  PubMed  Google Scholar 

  44. Ting LS, Decarie D, Ensom MH. Effect of acidification on protein binding of mycophenolic acid. Ther Drug Monit. 2007;29(1):132–3.

    CAS  PubMed  Google Scholar 

  45. LIXOFT. Monolix Suite 2018. http://www.lixoft.com. Accessed 01 Jun 2018.

  46. Kiang TKL, Sherwin CM, Spigarelli MG, Ensom MHH. Fundamentals of population pharmacokinetic modelling: modelling and software. Clin Pharmacokinet. 2012;51(8):515–25.

    CAS  PubMed  Google Scholar 

  47. Sherwin CM, Kiang TKL, Spigarelli MG, Ensom MHH. Fundamentals of population pharmacokinetic modelling: validation methods. Clin Pharmacokinet. 2012;51(9):573–90.

    PubMed  Google Scholar 

  48. Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development. CPT Pharmacometrics Syst Pharmacol. 2012;1:e6.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Rong Y, Mayo P, Ensom MHH, Kiang TKL. Population pharmacokinetic analysis of immediate-release oral tacrolimus co-administered with mycophenolate mofetil in corticosteroid-free adult kidney transplant recipients. Eur J Drug Metab Pharmacokinet. 2018. https://doi.org/10.1007/s13318-018-0525-3.

    Article  Google Scholar 

  50. R Core Team. R software v3.4.2. 2018. https://www.R-project.org. Accessed 02 Aug 2018.

  51. Savic RM, Karlsson MO. Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions. AAPS J. 2009;11(3):558–69.

    PubMed  PubMed Central  Google Scholar 

  52. Tedesco-Silva H, Bastien MC, Choi L, Felipe C, Campestrini J, Picard F, 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.

    CAS  PubMed  Google Scholar 

  53. Usui T, Kuno T, Mizutani T. Induction of human UDP-glucuronosyltransferase 1A1 by cortisol-GR. Mol Biol Rep. 2006;33(2):91–6.

    CAS  PubMed  Google Scholar 

  54. Kanou M, Usui T, Ueyama H, Sato H, Ohkubo I, Mizutani T. Stimulation of transcriptional expression of human UDP-glucuronosyltransferase 1A1 by dexamethasone. Mol Biol Rep. 2004;31(3):151–8.

    CAS  PubMed  Google Scholar 

  55. Ashraf MN, Asghar MW, Rong Y, Doschak MR, Kiang TKL. Advanced in vitro HepaRG culture systems for xenobiotic metabolism and toxicity characterization. Eur J Drug Metab Pharmacokinet. 2018;78:98. https://doi.org/10.1007/s13318-018-0533-3.

    Article  CAS  Google Scholar 

  56. Mackenzie PI. Identification of uridine diphosphate glucuronosyltransferases involved in the metabolism and clearance of mycophenolic acid. Ther Drug Monit. 2000;22(1):10–3.

    CAS  PubMed  Google Scholar 

  57. Miles KK, Stern ST, Smith PC, Kessler FK, Ali S, Ritter JK. An investigation of human and rat liver microsomal mycophenolic acid glucuronidation: evidence for a principal role of UGT1A enzymes and species differences in UGT1A specificity. Drug Metab Dispos. 2005;33(10):1513–20.

    CAS  PubMed  Google Scholar 

  58. Bernard O, Guillemette C. The main role of UGT1A9 in the hepatic metabolism of mycophenolic acid and the effects of naturally occurring variants. Drug Metab Dispos. 2004;32(8):775–8.

    CAS  PubMed  Google Scholar 

  59. Picard N, Ratanasavanh D, Premaud A, Le Meur Y, Marquet P. Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism. Drug Metab Dispos. 2005;33(1):139–46.

    CAS  PubMed  Google Scholar 

  60. Bernard O, Tojcic J, Journault K, Perusse L, Guillemette C. Influence of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronides of mycophenolic acid. Drug Metab Dispos. 2006;34(9):1539–45.

    CAS  PubMed  Google Scholar 

  61. Johnson LA, Oetting WS, Basu S, Prausa S, Matas A, Jacobson PA. Pharmacogenetic effect of the UGT polymorphisms on mycophenolate is modified by calcineurin inhibitors. Eur J Clin Pharmacol. 2008;64(11):1047–56.

    CAS  PubMed  Google Scholar 

  62. Vanhove T, Bouwsma H, Hilbrands L, Swen JJ, Spriet I, Annaert P, et al. Determinants of the magnitude of interaction between tacrolimus and voriconazole/posaconazole in solid organ recipients. Am J Transplant. 2017;17(9):2372–80.

    CAS  PubMed  Google Scholar 

  63. Atcheson BA, Taylor PJ, Kirkpatrick CM, et al. Free mycophenolic acid should be monitored in renal transplant recipients with hypoalbuminemia. Ther Drug Monit. 2004;26(3):284–6.

    CAS  PubMed  Google Scholar 

  64. Li P, Shuker N, Hesselink DA, van Schaik RH, Zhang X, van Gelder T. Do Asian renal transplant patients need another mycophenolate mofetil dose compared with Caucasian or African American patients? Transpl Int. 2014;27(10):994–1004.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Pharmacy and Pharmaceutical Sciences, Katz Group Centre for Pharmacy and Health Research, University of Alberta, Room 3-142D, 11361-87 Ave, Edmonton, AB, T6G 2E1, Canada

    Yan Rong, Patrick Mayo & Tony K. L. Kiang

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

    Mary H. H. Ensom

Authors
  1. Yan Rong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrick Mayo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mary H. H. Ensom
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tony K. L. Kiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tony K. L. Kiang.

Ethics declarations

Funding

This study was supported by an unrestricted educational Grant from Hoffmann-La Roche Limited (principal investigator: Mary H. H. Ensom) and the 2015 Vancouver Coastal Health Research Institute Team Grant Award (principal investigator: Tony K. L. Kiang).

Conflict of interest

Yan Rong and Patrick Mayo have no conflicts of interest that are directly related to the content of this article. Tony K. L. Kiang and Mary H. H. Ensom received grants as detailed above (which were not in conflict of interest with this article), and do not report any other conflicts of interest.

Ethics Approval

All procedures in this study were in accordance with the 1964 Helsinki Declaration (and its amendments). Ethics and operation approvals were obtained from both the University of British Columbia and University of Alberta Clinical Research Ethics Boards and the Vancouver Coastal Health Research Institute.

Consent to Participate

Written informed consent was obtained from all individual participants included in the study.

Data Availability

Original data can be made available upon request to the corresponding author.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rong, Y., Mayo, P., Ensom, M.H.H. et al. Population Pharmacokinetics of Mycophenolic Acid Co-Administered with Tacrolimus in Corticosteroid-Free Adult Kidney Transplant Patients. Clin Pharmacokinet 58, 1483–1495 (2019). https://doi.org/10.1007/s40262-019-00771-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-019-00771-3

Search

Navigation