Skip to main content

Advertisement

SpringerLink
Log in

Pharmacokinetics of mycophenolic acid and external evaluation of two limited sampling strategies of drug exposure in patients with juvenile systematic lupus erythematosus

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

Abstract

Introduction

Mycophenolate mofetil (MMF), a pro-drug of mycophenolic acid (MPA), has become a major therapeutic option in juvenile systemic lupus erythematosus (jSLE). Monitoring MPA exposure using area under curve (AUC) has proved its value to increase efficacy and safety in solid organ transplantation both in children and adults, but additional data are required in patients with autoimmune diseases. In order to facilitate MMF therapeutic drug monitoring (TDM) in children, Bayesian estimators (BE) of MPA AUC0–12 h using limited sampling strategies (LSS) have been developed. Our aim was to conduct an external validation of these LSS using rich pharmacokinetics and compare their predictive performance.

Methods

Pharmacokinetic blood samples were collected from jSLE treated by MMF and MPA plasma concentrations were determined using high-performance liquid chromatography system with ultraviolet detection (HPLC–UV). Individual AUC0–12 h at steady state was calculated using the trapezoid rule and compared with two LSS: (1) ISBA, a two-stage Bayesian approach developed for jSLE and (2) ADAPT, a non-linear mixed effects model with a parametric maximum likelihood approach developed with data from renal transplanted adults.

Results

We received 41 rich pediatric PK at steady state from jSLE and calculated individual AUC0–12 h. The external validation MPA AUC0–12 h was conducted by selecting the concentration–time points adapted to ISBA and ADAPT: (1) ISBA showed good accuracy (bias: − 0.8 mg h/L), (2) ADAPT resulted in a bias of 6.7 mg L/h. The corresponding relative root mean square prediction error (RSME) was 23% and 43% respectively.

Conclusion

According to our external validation of two LSS of drug exposure, the ISBA model is recommended for Bayesian estimation of MPA AUC0–12 h in jSLE. In the literature focusing on MMF TDM, an efficacy cut-off for MPA AUC0–12 h between 30 and 45 mg h/L is proposed in jSLE but this requires additional validation.

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

Similar content being viewed by others

References

  1. Smith EMD, Lythgoe H, Midgley A, Beresford MW, Hedrich CM (2019) Juvenile-onset systemic lupus erythematosus: update on clinical presentation, pathophysiology and treatment options. Clin Immunol 209:108274. https://doi.org/10.1016/j.clim.2019.108274

    Article  CAS  PubMed  Google Scholar 

  2. Groot N, de Graeff N, Marks SD et al (2017) European evidence-based recommendations for the diagnosis and treatment of childhood-onset lupus nephritis: the SHARE initiative. Ann Rheum Dis 76(12):1965–1973. https://doi.org/10.1136/annrheumdis-2017-211898

    Article  CAS  PubMed  Google Scholar 

  3. Bennett M, Brunner HI (2013) Biomarkers and updates on pediatrics lupus nephritis. Rheum Dis Clin North Am 39(4):833–853. https://doi.org/10.1016/j.rdc.2013.05.001

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bernatsky S, Boivin J-F, Joseph L et al (2006) Mortality in systemic lupus erythematosus. Arthritis Rheum 54(8):2550–2557. https://doi.org/10.1002/art.21955

    Article  CAS  PubMed  Google Scholar 

  5. Hedrich CM, Smith EMD, Beresford MW (2017) Juvenile-onset systemic lupus erythematosus (jSLE) - pathophysiological concepts and treatment options. Best Pract Res Clin Rheumatol 31(4):488–504. https://doi.org/10.1016/j.berh.2018.02.001

    Article  PubMed  Google Scholar 

  6. Mok CC (2017) Therapeutic monitoring of the immuno-modulating drugs in systemic lupus erythematosus. Expert Rev Clin Immunol 13(1):35–41. https://doi.org/10.1080/1744666X.2016.1212659

    Article  CAS  PubMed  Google Scholar 

  7. Godron-Dubrasquet A, Woillard J-B, Decramer S et al (2021) Mycophenolic acid area under the concentration-time curve is associated with therapeutic response in childhood-onset lupus nephritis. Pediatr Nephrol 36(2):341–347. https://doi.org/10.1007/s00467-020-04733-x

    Article  PubMed  Google Scholar 

  8. Benz MR, Ehren R, Kleinert D et al (2019) Generation and validation of a limited sampling strategy to monitor mycophenolic acid exposure in children with nephrotic syndrome. Ther Drug Monit 41(6):696–702. https://doi.org/10.1097/FTD.0000000000000671

    Article  CAS  PubMed  Google Scholar 

  9. Allison AC, Eugui EM (2000) Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 47(2):85–118. https://doi.org/10.1016/S0162-3109(00)00188-0

    Article  CAS  PubMed  Google Scholar 

  10. Sagcal-Gironella ACP, Fukuda T, Wiers K et al (2011) Pharmacokinetics and pharmacodynamics of mycophenolic acid and their relation to response to therapy of childhood onset systemic lupus erythematosus. Semin Arthritis Rheum 40(4):307–313. https://doi.org/10.1016/j.semarthrit.2010.05.007

    Article  CAS  PubMed  Google Scholar 

  11. Ehren R, Schijvens AM, Hackl A, Schreuder MF, Weber LT (2021) Therapeutic drug monitoring of mycophenolate mofetil in pediatric patients: novel techniques and current opinion. Expert Opin Drug Metab Toxicol 17(2):201–213. https://doi.org/10.1080/17425255.2021.1843633

    Article  CAS  PubMed  Google Scholar 

  12. Bullingham RES, Nicholls AJ, Kamm BR (1998) Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 34(6):429–455. https://doi.org/10.2165/00003088-199834060-00002

    Article  CAS  PubMed  Google Scholar 

  13. Benjanuwattra J, Pruksakorn D, Koonrungsesomboon N (2020) Mycophenolic acid and its pharmacokinetic drug-drug interactions in humans: review of the evidence and clinical implications. J Clin Pharmacol 60(3):295–311. https://doi.org/10.1002/jcph.1565

    Article  CAS  PubMed  Google Scholar 

  14. Oni L, Wright RD, Marks S, Beresford MW, Tullus K (2021) Kidney outcomes for children with lupus nephritis. Pediatr Nephrol 36(6):1377–1385. https://doi.org/10.1007/s00467-020-04686-1. Epub 2020 Jul 28

  15. van Gelder T, Berden JHM, Berger SP (2015) To TDM or not to TDM in lupus nephritis patients treated with MMF? Nephrol Dial Transplant 30(4):560–564. https://doi.org/10.1093/ndt/gfu184

    Article  CAS  PubMed  Google Scholar 

  16. Bergan S, Brunet M, Hesselink DA et al (2021) Personalized therapy for mycophenolate: consensus report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Ther Drug Monit 43(2):150–200. https://doi.org/10.1097/FTD.0000000000000871

    Article  CAS  PubMed  Google Scholar 

  17. Woillard J-B, Bader-Meunier B, Salomon R et al (2014) Pharmacokinetics of mycophenolate mofetil in children with lupus and clinical findings in favour of therapeutic drug monitoring. Br J Clin Pharmacol 78(4):867–876. https://doi.org/10.1111/bcp.12392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Premaud A, Le Meur Y, Debord J et al (2005) Maximum a posteriori Bayesian estimation of MPA pharmacokinetics in renal transplant recipients at different postgrafting periods. Ther Drug Monit 27:354–361

    Article  CAS  Google Scholar 

  19. Premaud A, Debord J, Rousseau A et al (2005) A double absorption-phase model adequately describes mycophenolic acid plasma profiles in de novo renal transplant recipients given oral mycophenolate mofetil. Clin Pharmacokinet 44:837–847

    Article  CAS  Google Scholar 

  20. Hulin A, Blanchet B, Audard V et al (2009) Comparison of 3 estimation methods of mycophenolic acid AUC based on a limited sampling strategy in renal transplant patients. Ther Drug Monit 31(2):224–232. https://doi.org/10.1097/FTD.0b013e31819c077c

    Article  CAS  PubMed  Google Scholar 

  21. Payen S, Zhang D, Maisin A et al (2005) Population pharmacokinetics of mycophenolic acid in kidney transplant pediatric and adolescent patients. Ther Drug Monit 27(3):378–388. https://doi.org/10.1097/01.ftd.0000159784.25872.f6

    Article  CAS  PubMed  Google Scholar 

  22. Pharmacology of ImmunoSuppressive Drugs and of Transplantation (PIST) - ISBA (Immunosuppressants Bayesian Adaptation) Website. Availale at: https://www.unilim.fr/ippritt/research/axis-i/pharmacokinetics

  23. Djabarouti S, Breilh D, Duffau P et al (2010) Steady-state mycophenolate mofetil pharmacokinetic parameters enable prediction of systemic lupus erythematosus clinical flares: an observational cohort study. Arthritis Res Ther 12(6):R217. https://doi.org/10.1186/ar3202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lertdumrongluk P, Somparn P, Kittanamongkolchai W, Traitanon O, Vadcharavivad S, Avihingsanon Y (2010) Pharmacokinetics of mycophenolic acid in severe lupus nephritis. Kidney Int 78(4):389–395. https://doi.org/10.1038/ki.2010.170

    Article  CAS  PubMed  Google Scholar 

  25. Pourafshar N, Karimi A, Wen X et al (2019) The utility of trough mycophenolic acid levels for the management of lupus nephritis. Nephrol Dial Transplant 34(1):83–89. https://doi.org/10.1093/ndt/gfy026

    Article  CAS  PubMed  Google Scholar 

  26. Saint-Marcoux F, Vandierdonck S, Prémaud A, Debord J, Rousseau A, Marquet P (2011) Large scale analysis of routine dose adjustments of mycophenolate mofetil based on global exposure in renal transplant patients. Ther Drug Monit 33(3):285–294. https://doi.org/10.1097/FTD.0b013e31821633a6

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kuypers DRJ, Meur YL, Cantarovich M et al (2010) Consensus report on therapeutic drug monitoring of mycophenolic acid in solid organ transplantation. CJASN 5(2):341–358. https://doi.org/10.2215/CJN.07111009

    Article  CAS  PubMed  Google Scholar 

  28. Saint-Marcoux F, Guigonis V, Decramer S et al (2011) Development of a Bayesian estimator for the therapeutic drug monitoring of mycophenolate mofetil in children with idiopathic nephrotic syndrome. Pharmacol Res 63(5):423–431. https://doi.org/10.1016/j.phrs.2011.01.009

    Article  CAS  PubMed  Google Scholar 

  29. Tellier S, Dallocchio A, Guigonis V et al (2016) Mycophenolic acid pharmacokinetics and relapse in children with steroid–dependent idiopathic nephrotic syndrome. Clin J Am Soc Nephrol 11(10):1777–1782. https://doi.org/10.2215/CJN.00320116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kiang TKL, Ensom MHH (2016) Therapeutic drug monitoring of mycophenolate in adult solid organ transplant patients: an update. Expert Opin Drug Metab Toxicol 12(5):545–553. https://doi.org/10.1517/17425255.2016.1170806

    Article  CAS  PubMed  Google Scholar 

  31. Zhao W, Elie V, Baudouin V et al (2010) Population pharmacokinetics and Bayesian estimator of mycophenolic acid in children with idiopathic nephrotic syndrome. Br J Clin Pharmacol 69(4):358–366. https://doi.org/10.1111/j.1365-2125.2010.03615.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zahr N, Amoura Z, Debord J et al (2008) Pharmacokinetic study of mycophenolate mofetil in patients with systemic lupus erythematosus and design of Bayesian estimator using limited sampling strategies. Clin Pharmacokinet 47(4):277–284. https://doi.org/10.2165/00003088-200847040-00005

    Article  CAS  PubMed  Google Scholar 

  33. de Winter BCM, Neumann I, van Hest RM, van Gelder T, Mathot RAA (2009) Limited sampling strategies for therapeutic drug monitoring of mycophenolate mofetil therapy in patients with autoimmune disease. Ther Drug Monit 31(3):382–390. https://doi.org/10.1097/FTD.0b013e3181a23f1a

    Article  CAS  PubMed  Google Scholar 

  34. Neumann I, Haidinger M, Jäger H et al (2003) Pharmacokinetics of mycophenolate mofetil in patients with autoimmune diseases compared renal transplant recipients. JASN 14(3):721–727. https://doi.org/10.1097/01.ASN.0000051598.12824.DA

    Article  CAS  PubMed  Google Scholar 

  35. Zahr N, Arnaud L, Marquet P et al (2010) Mycophenolic acid area under the curve correlates with disease activity in lupus patients treated with mycophenolate mofetil. Arthritis Rheum. https://doi.org/10.1002/art.27495

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the pediatricians and nurses of the departments of pediatrics and nephrology who take care of the patients and their family.

Author information

Authors and Affiliations

  1. Paediatric Pharmacology, Department of Biological Pharmacology, Saint-Louis University Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France

    Quentin Beaulieu, Daolun Zhang, Lauriane Goldwirst & Evelyne Jacqz-Aigrain

  2. General Pediatrics, Infectious Disease and Internal Medicine Department, Robert Debre University Hospital, Reference Center for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), AP-HP, Paris, France

    Isabelle Melki

  3. Pediatric Hematology-Immunology and Rheumatology Department, Necker-Enfants Malades University Hospital, Reference center for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), AP-HP, Paris, France

    Isabelle Melki

  4. Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, Paris, France

    Isabelle Melki

  5. Department of Pediatric Nephrology, Robert Debré University Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France

    Véronique Baudouin

  6. IPPRITT, INSERM, U1248, Limoges, France

    Jean-Baptiste Woillard

  7. IPPRITT, University of Limoges, Limoges, France

    Jean-Baptiste Woillard

  8. Department of Pharmacology and Toxicology, CHU Limoges, Limoges, France

    Jean-Baptiste Woillard

  9. University of Paris, Paris, France

    Evelyne Jacqz-Aigrain

  10. Department of Biological Pharmacology, Saint-Louis University Hospital, Assistance Publique - Hôpitaux de Paris, FranceHôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, 1 avenue Charles Vellefaux, Paris, 75010, France

    Evelyne Jacqz-Aigrain

Authors
  1. Quentin Beaulieu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daolun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Isabelle Melki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Véronique Baudouin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lauriane Goldwirst
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jean-Baptiste Woillard
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Evelyne Jacqz-Aigrain
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

QB performed data analysis and wrote the first draft of the manuscript, DZ collected the patients’ information and participated to data analysis, IM and VB are pediatricians taking care of the patients, LG participated to ADAPT analysis, JBW was responsible of ABIS analysis, EJA organized the study, EJA and JBW reviewed and finalized the manuscript, and all authors approved the submitted version.

Corresponding author

Correspondence to Evelyne Jacqz-Aigrain.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Beaulieu, Q., Zhang, D., Melki, I. et al. Pharmacokinetics of mycophenolic acid and external evaluation of two limited sampling strategies of drug exposure in patients with juvenile systematic lupus erythematosus. Eur J Clin Pharmacol 78, 1003–1010 (2022). https://doi.org/10.1007/s00228-022-03295-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-022-03295-1

Keywords

Search

Navigation