Advertisement

Clinical Pharmacokinetics

, Volume 53, Issue 12, pp 1161–1170 | Cite as

Assessment of the Relationship Between Methotrexate Polyglutamates in Red Blood Cells and Clinical Response in Patients Commencing Methotrexate for Rheumatoid Arthritis

  • Shan Pan
  • Lisa K. Stamp
  • Stephen B. Duffull
  • Murray L. Barclay
  • Judith M. Dalrymple
  • Jill Drake
  • Mei Zhang
  • Julia KorellEmail author
Original Research Article

Abstract

Background and Objectives

Therapeutic drug monitoring in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX, MTXGlu1) has not been established. In this study, we aim to explore the relationship between red blood cell (RBC) concentrations of MTX and its polyglutamate metabolites (MTXGlu n ; n = 2, 3, 4, 5) and clinical response in RA patients commencing MTX.

Methods

The binding activity of MTXGlu n to three putative enzymes involved in the MTX mechanism of action—dihydrofolate reductase, thymidylate synthase, and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase—was simulated. RBC MTXGlu n concentrations that gave the highest inhibition activity across all three enzymes were linked with the disease activity score DAS28-3v (C-reactive protein [CRP]). A population pharmacokinetic–pharmacodynamic model was developed to describe the relationship between RBC MTX polyglutamate concentrations and clinical response in 12 RA patients commencing MTX.

Results

The highest inhibition activity was with RBC MTXGlu3–5. These polyglutamates were further evaluated for their relationship with DAS28-3v (CRP). Three of the 12 patients had a high DAS28-3v (CRP) at baseline (mean = 6.1) and showed a delayed response to MTX treatment. The remaining nine patients with a lower DAS28-3v (CRP) baseline (mean = 3.6) showed an immediate response. The developed MTX pharmacokinetic–pharmacodynamic model provided an acceptable description of the observed DAS28-3v (CRP) across all patients.

Conclusions

The developed model describes a longitudinal relationship between RBC MTXGlu3–5 concentrations and DAS28-3v (CRP) in patients with RA commencing MTX. Further work is required to determine whether measurement of RBC MTX polyglutamates might be useful for dose individualisation in patients with RA.

Keywords

Rheumatoid Arthritis Rheumatoid Arthritis Patient Pharmacodynamic Model High Inhibition Activity Polyglutamates 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The clinical studies were supported by the Health Research Council of New Zealand and New Zealand Pharmacy Education and Research Foundation. Shan Pan was supported by a University of Otago PhD scholarship.

Ethical standards

The clinical studies were approved by the Upper South B Regional Ethics Committee and were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

All patients gave written informed consent prior to entering the clinical studies.

Conflicts of interest

Shan Pan, Lisa K. Stamp, Stephen B. Duffull, Murray L. Barclay, Judith M. Dalrymple, Jill Drake, Mei Zhang and Julia Korell declare no conflicts of interest.

Supplementary material

40262_2014_179_MOESM1_ESM.pdf (358 kb)
Supplementary material 1 (PDF 358 kb)

References

  1. 1.
    Lambert CM, Sandhu S, Lochhead A, Hurst NP, McRorie E, Dhillon V. Dose escalation of parenteral methotrexate in active rheumatoid arthritis that has been unresponsive to conventional doses of methotrexate: a randomized, controlled trial. Arthritis Rheum. 2004;50(2):364–71.PubMedCrossRefGoogle Scholar
  2. 2.
    Lafforgue P, Monjanel-Mouterde S, Durand A, Catalin J, Acquaviva PC. Lack of correlation between pharmacokinetics and efficacy of low dose methotrexate in patients with rheumatoid arthritis. J Rheumatol. 1995;22(5):844–9.PubMedGoogle Scholar
  3. 3.
    Halilova KI, Brown EE, Morgan SL, Bridges SL Jr, Hwang MH, Arnett DK, et al. Markers of treatment response to methotrexate in rheumatoid arthritis: where do we stand? Int J Rheumatol. 2012;2012:978396–402. doi: 10.1155/2012/978396.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Stamp L, Roberts R, Kennedy M, Barclay M, O’Donnell J, Chapman P. The use of low dose methotrexate in rheumatoid arthritis: are we entering a new era of therapeutic drug monitoring and pharmacogenomics? Biomed Pharmacother. 2006;60(10):678–87.PubMedCrossRefGoogle Scholar
  5. 5.
    Cronstein BN, Naime D, Ostad E. The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. J Clin Invest. 1993;92(6):2675–82. doi: 10.1172/jci116884.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis. 2001;60(8):729–35. doi: 10.1136/ard.60.8.729.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    van Haandel L, Leeder JS, Becker ML. Measurement of methotrexate metabolites in peripheral blood mononuclear cells in juvenile idiopathic arthritis: a more relevant cellular biomarker for drug response? Arthritis Rheum. 2011;63(10):S95.Google Scholar
  8. 8.
    Angelis-Stoforidis P, Vajda FJE, Christophidis N. Methotrexate polyglutamate levels in circulating erythrocytes and polymorphs correlate with clinical efficacy in rheumatoid arthritis. Clin Exp Rheumatol. 1999;17(3):313–20.PubMedGoogle Scholar
  9. 9.
    Hobl EL, Jilma B, Erlacher L, Duhm B, Mustak M, Broll H, et al. A short-chain methotrexate polyglutamate as outcome parameter in rheumatoid arthritis patients receiving methotrexate. Clin Exp Rheumatol. 2012;30(2):156–63.PubMedGoogle Scholar
  10. 10.
    Dervieux T, Furst D, Lein DO, Capps R, Smith K, Walsh M, et al. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum. 2004;50(9):2766–74. doi: 10.1002/art.20460.PubMedCrossRefGoogle Scholar
  11. 11.
    Dervieux T, Furst D, Lein D, Capps R, Smith K, Caldwell J, et al. Pharmacogenetic and metabolite measurements are associated with clinical status in patients with rheumatoid arthritis treated with methotrexate: results of a multicentred cross sectional observational study. Ann Rheum Dis. 2005;64(8):1180–5.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Stamp LK, Barclay ML, O’Donnell JL, Zhang M, Drake J, Frampton C, et al. Effects of changing from oral to subcutaneous methotrexate on red blood cell methotrexate polyglutamate concentrations and disease activity in patients with rheumatoid arthritis. J Rheumatol. 2011;38(12):2540–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Dalrymple JM, Stamp LK, O’Donnell JL, Chapman PT, Zhang M, Barclay ML. Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 2008;58(11):3299–308.PubMedCrossRefGoogle Scholar
  14. 14.
    Lee YJ, Krishnaswami S, Harnisch L, French J, Park K, editors. Model-based evaluation of DAS28 as a potential surrogate for ACR20 to establish the dose-response relationship for disease modifying anti-rheumatic drugs. A case study using tasocitinib (CP-690,550), an oral JAK inhibitor. http://www.page-meeting.org/?abstract=1704. Population Approach Group in Europe (PAGE); 2012, Berlin.
  15. 15.
    Fransen J, van Riel PLCM. The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol. 2005;23(5 Suppl 39):S93–9.PubMedGoogle Scholar
  16. 16.
    Korell J, Stamp LK, Barclay ML, Dalrymple JM, Drake J, Zhang M, et al. A population pharmacokinetic model for low-dose methotrexate and its polyglutamated metabolites in red blood cells. Clin Pharmacokinet. 2013;52(6):475–85.PubMedCrossRefGoogle Scholar
  17. 17.
    Appleman JR, Prendergast N, Delcamp TJ, Freisheim JH, Blakley RL. Kinetics of the formation and isomerization of methotrexate complexes of recombinant human dihydrofolate reductase. J Biol Chem. 1988;263(21):10304–13.PubMedGoogle Scholar
  18. 18.
    Allegra CJ, Chabner BA, Drake JC, Lutz R, Rodbard D, Jolivet J. Enhanced inhibition of thymidylate synthase by methotrexate polyglutamates. J Biol Chem. 1985;260(17):9720–6.PubMedGoogle Scholar
  19. 19.
    Allegra CJ, Drake JC, Jolivet J, Chabner BA. Inhibition of phosphoribosylaminoimidazolecarboxamide transformylase by methotrexate and dihydrofolic acid polyglutamates. Proc Natl Acad Sci USA. 1985;82(15):4881–5. doi: 10.1073/pnas.82.15.4881.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Duffull SB, Wright DFB, Winter HR. Interpreting population pharmacokinetic-pharmacodynamic analyses: a clinical viewpoint. Br J Clin Pharmacol. 2011;71(6):807–14. doi: 10.1111/j.1365-2125.2010.03891.x.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Zhang LP, Beal SL, Sheiner LB. Simultaneous vs. sequential analysis for population PK/PD data I: best-case performance. J Pharmacokinet Pharmacodyn. 2003;30(6):387–404. doi: 10.1023/B:JOPA.0000012998.04442.1f.PubMedCrossRefGoogle Scholar
  22. 22.
    Savic RM, Jonker DM, Kerbusch T, Karlsson MO. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn. 2007;34(5):711–26. doi: 10.1007/s10928-007-9066-0.PubMedCrossRefGoogle Scholar
  23. 23.
    Stamp L, O’Donnell J, Chapman P, Zhang M, James J, Frampton C, et al. Methotrexate polyglutamate concentrations are not associated with disease control in rheumatoid arthritis patients receiving long-term methotrexate therapy. Arthritis Rheum. 2010;62(2):359–68. doi: 10.1002/art.27201.PubMedCrossRefGoogle Scholar
  24. 24.
    Dervieux T, Greenstein N, Kremer J. Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum. 2006;54(10):3095–103.PubMedCrossRefGoogle Scholar
  25. 25.
    Bulatovic Calasan M, den Boer E, de Rotte MC, Vastert SJ, Kamphuis S, de Jonge R, et al. Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in juvenile idiopathic arthritis patients. Ann Rheum Dis. 2013;28(10):203723.Google Scholar
  26. 26.
    Anderson JJ, Wells G, Verhoeven AC, Felson DT. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum. 2000;43(1):22–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Oliver JE, Silman AJ. Risk factors for the development of rheumatoid arthritis. Scand J Rheumatol. 2006;35(3):169–74. doi: 10.1080/03009740600718080.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Shan Pan
    • 1
  • Lisa K. Stamp
    • 2
  • Stephen B. Duffull
    • 1
  • Murray L. Barclay
    • 2
    • 3
  • Judith M. Dalrymple
    • 3
  • Jill Drake
    • 2
  • Mei Zhang
    • 2
    • 4
  • Julia Korell
    • 5
    • 6
    Email author
  1. 1.School of PharmacyUniversity of OtagoDunedinNew Zealand
  2. 2.Department of MedicineUniversity of OtagoChristchurchNew Zealand
  3. 3.Department of Clinical PharmacologyChristchurch HospitalChristchurchNew Zealand
  4. 4.Toxicology, Canterbury Health LaboratoriesChristchurchNew Zealand
  5. 5.Department of Pharmaceutical BiosciencesUppsala UniversityUppsalaSweden
  6. 6.Model Answers Pty LtdBrisbaneAustralia

Personalised recommendations