Clinical Pharmacokinetics

, Volume 57, Issue 5, pp 547–558 | Cite as

Population Pharmacokinetics of Mycophenolic Acid: An Update

Review Article

Abstract

The most recent comprehensive reviews on the population pharmacokinetics of mycophenolic acid (MPA) were published in 2014. Since then, several population pharmacokinetic studies on MPA have been published. The majority of literature is still focused on the kidney transplant population, although studies have also been conducted in liver and lung transplantation, autoimmune diseases, and hematopoietic stem cell transplant. While the majority of the model building is still based on parametric non-linear mixed-effects modeling, recent studies suggest the suitability of other methodologies. Additionally, instead of just focusing on pharmacokinetic modeling, a trend toward describing the relationships between pharmacokinetic and pharmacodynamic parameters is observed. Given the importance of enterohepatic recirculation (EHR) in the pharmacokinetics of MPA, more authors have attempted to characterize this process in their models. Overall, the recent models have become more sophisticated and incorporate EHR, pharmacodynamic relationships, and metabolites while maintaining many of the population values and covariates identified previously. However, the number of MPA population pharmacokinetic models describing the enteric-coated formulation of MPA (EC-MPA) is still limited. Given the increasing use of EC-MPA, more studies are needed to fill this literature gap. In addition, few studies are yet available characterizing free MPA concentration or MPA metabolites. Given the extensive protein binding, low to intermediate extraction, and intrinsic clearance characteristics of MPA in humans, including these variables would improve the population structural models.

Notes

Compliance with Ethical Standards

Conflicts of interest

Tony K. L. Kiang and Mary H. H. Ensom have no conflicts of interests to declare.

Funding

No funding was received for the preparation of this article.

References

  1. 1.
    Staatz CE, Tett SE. Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update. Arch Toxicol. 2014;88(7):1351–89.CrossRefPubMedGoogle Scholar
  2. 2.
    Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in solid organ transplant recipients. Clin Pharmacokinet. 2007;46(1):13–58.CrossRefPubMedGoogle Scholar
  3. 3.
    Abd Rahman AN, Tett SE, Staatz CE. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease. Clin Pharmacokinet. 2013;52(5):303–31.CrossRefPubMedGoogle Scholar
  4. 4.
    Zhang D, Chow DS. Clinical pharmacokinetics of mycophenolic acid in hematopoietic stem cell transplantation recipients. Eur J Drug Metab Pharmacokinet. 2017;42(2):183–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus. 2005;14(Suppl 1):s2–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Kiang TK, Ensom MH. Therapeutic drug monitoring of mycophenolate in adult solid organ transplant patients: an update. Expert Opin Drug Metab Toxicol. 2016;12(5):545–53.CrossRefPubMedGoogle Scholar
  7. 7.
    Tett SE, Saint-Marcoux F, Staatz CE, Brunet M, Vinks AA, Miura M, et al. Mycophenolate, clinical pharmacokinetics, formulations, and methods for assessing drug exposure. Transplant Rev (Orlando). 2011;25(2):47–57.CrossRefGoogle Scholar
  8. 8.
    Kiang TK, Sherwin CM, Spigarelli MG, Ensom MH. Fundamentals of population pharmacokinetic modelling: modelling and software. Clin Pharmacokinet. 2012;51(8):515–25.CrossRefGoogle Scholar
  9. 9.
    Sherwin CM, Kiang TK, Spigarelli MG, Ensom MH. Fundamentals of population pharmacokinetic modelling: validation methods. Clin Pharmacokinet. 2012;51(9):573–90.CrossRefPubMedGoogle Scholar
  10. 10.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Dong M, Fukuda T, Vinks AA. Optimization of mycophenolic acid therapy using clinical pharmacometrics. Drug Metab Pharmacokinet. 2014;29(1):4–11.CrossRefPubMedGoogle Scholar
  12. 12.
    Zeng L, Blair EY, Nath CE, Shaw PJ, Earl JW, Stephen K, et al. Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantation. Br J Clin Pharmacol. 2010;70(4):567–79.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Premaud A, Weber LT, Tonshoff B, Armstrong VW, Oellerich M, Urien S, et al. Population pharmacokinetics of mycophenolic acid in pediatric renal transplant patients using parametric and nonparametric approaches. Pharmacol Res. 2011;63(3):216–24.CrossRefPubMedGoogle Scholar
  14. 14.
    Dong M, Fukuda T, Cox S, de Vries MT, Hooper DK, Goebel J, et al. Population pharmacokinetic–pharmacodynamic modelling of mycophenolic acid in paediatric renal transplant recipients in the early post-transplant period. Br J Clin Pharmacol. 2014;78(5):1102–12.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    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.CrossRefPubMedGoogle Scholar
  16. 16.
    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.CrossRefPubMedGoogle Scholar
  17. 17.
    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.CrossRefPubMedGoogle Scholar
  18. 18.
    Veliĉković-Radovanović 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.CrossRefPubMedGoogle Scholar
  19. 19.
    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.CrossRefPubMedGoogle Scholar
  20. 20.
    Langers P, Press RR, Inderson A, Cremers SC, den Hartigh J, Baranski AG, et al. Limited sampling model for advanced mycophenolic acid therapeutic drug monitoring after liver transplantation. Ther Drug Monit. 2014;36(2):141–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Filler G, Zimmering M, Mai I. Pharmacokinetics of mycophenolate mofetil are influenced by concomitant immunosuppression. Pediatr Nephrol. 2000;14(2):100–4.CrossRefPubMedGoogle Scholar
  22. 22.
    Pou L, Brunet M, Cantarell C, Vidal E, Oppenheimer F, Monforte V, et al. Mycophenolic acid plasma concentrations: influence of comedication. Ther Drug Monit. 2001;23(1):35–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Wang XX, Feng MR, Nguyen H, Smith DE, Cibrik DM, Park JM. Population pharmacokinetics of mycophenolic acid in lung transplant recipients with and without cystic fibrosis. Eur J Clin Pharmacol. 2015;71(6):673–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Wang XX, Liu W, Zheng T, Park JM, Smith DE, Feng MR. Population pharmacokinetics of mycophenolic acid and its glucuronide metabolite in lung transplant recipients with and without cystic fibrosis. Xenobiotica. 2017;47(8):697–704.CrossRefPubMedGoogle Scholar
  25. 25.
    Saint-Marcoux F, Guigonis V, Decramer S, Gandia P, Ranchin B, Parant F, et al. Development of a Bayesian estimator for the therapeutic drug monitoring of mycophenolate mofetil in children with idiopathic nephrotic syndrome. Pharmacol Res. 2011;63(5):423–31.CrossRefPubMedGoogle Scholar
  26. 26.
    Woillard JB, Bader-Meunier B, Salomon R, Ranchin B, Decramer S, Fischbach M, et al. Pharmacokinetics of mycophenolate mofetil in children with lupus and clinical findings in favour of therapeutic drug monitoring. Br J Clin Pharmacol. 2014;78(4):867–76.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Abd Rahman AN, Tett SE, Abdul Gafor HA, McWhinney BC, Staatz CE. Development of improved dosing regimens for mycophenolate mofetil based on population pharmacokinetic analyses in adults with lupus nephritis. Eur J Drug Metab Pharmacokinet. doi: 10.1007/s13318-017-0420-3.
  28. 28.
    Kuypers DR, Ekberg H, Grinyo J, Nashan B, Vincenti F, Snell P, et al. Mycophenolic acid exposure after administration of mycophenolate mofetil in the presence and absence of cyclosporin in renal transplant recipients. Clin Pharmacokinet. 2009;48(5):329–41.CrossRefPubMedGoogle Scholar
  29. 29.
    Li H, Mager DE, Sandmaier BM, Storer BE, Boeckh MJ, Bemer MJ, et al. Pharmacokinetic and pharmacodynamic analysis of inosine monophosphate dehydrogenase activity in hematopoietic cell transplantation recipients treated with mycophenolate mofetil. Biol Blood Marrow Transplant. 2014;20(8):1121–9.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Faculty of Pharmacy and Pharmaceutical SciencesUniversity of AlbertaEdmontonCanada
  2. 2.Faculty of Pharmaceutical SciencesUniversity of British ColumbiaVancouverCanada
  3. 3.Pharmacy Department (0B7)Children’s and Women’s Health Centre of British ColumbiaVancouverCanada

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