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Non-Linear Rituximab Pharmacokinetics and Complex Relationship between Rituximab Concentrations and Anti-Neutrophil Cytoplasmic Antibodies (ANCA) in ANCA-Associated Vasculitis: The RAVE Trial Revisited

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Abstract

Background and Objectives

Rituximab is approved in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and leads to a decrease of ANCA levels. The objectives of this study were to investigate the non-linear pharmacokinetics of rituximab and the relationship between its concentrations and ANCA levels in AAV patients.

Methods

Ninety-two AAV patients from the RAVE (Rituximab in ANCA-Associated Vasculitis) trial were assessed. Both ANCA anti-myeloperoxidase (MPO-ANCA) and anti-proteinase 3 (PR3-ANCA) levels were used as biomarkers. The pharmacokinetics of rituximab were described using a semi-mechanistic two-compartment model that included a latent target antigen turnover and allowed the estimation of specific target-mediated elimination in addition to its non-specific elimination of rituximab. The effect of rituximab on the ANCA level was described using a semi-mechanistic compartment model with a negative feedback (Friberg) model with no transit compartment. A population modeling approach was used.

Results

Our pharmacokinetic and pharmacokinetic–pharmacodynamic (PK-PD) models satisfactorily described both concentration–time and concentration–effect relationship data. The mean (inter-individual standard deviation) estimated non-specific clearance was 0.15 L/day (0.30%) and the target-mediated elimination rate constant was 2.4 × 10−5 nmol/day. The elimination half-lives for MPO-ANCA and PR3-ANCA were 24 and 18 days, respectively.

Conclusions

A non-linear target-mediated elimination of rituximab was detected in AAV patients. Our PK-PD model allowed quantification of the association between rituximab concentrations and ANCA levels. This decrease was deep but delayed, and more sustained in patients with MPO-ANCA than in those with PR3-ANCA. Our results suggest that repeating courses of rituximab might improve the clinical response to rituximab.

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References

  1. Li J, Levi M, Charoin J-E, Frey N, Kheoh T, Ren S, et al. Rituximab exhibits a long half-life based on a population pharmacokinetic analysis in non-Hodgkin’s lymphoma (NHL) patients. Blood. 2007;110(11):2371.

    Google Scholar 

  2. Rozman S, Grabnar I, Novakovic S, Mrhar A, Jezersek Novakovic B. Population pharmacokinetics of rituximab in patients with diffuse large B-cell lymphoma and association with clinical outcome. Br J Clin Pharmacol. 2017;83(8):1782–90. https://doi.org/10.1111/bcp.13271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tout M, Gagez AL, Lepretre S, et al. Influence of FCGR3A-158 V/F genotype and baseline CD20 antigen count on target-mediated elimination of rituximab in patients with chronic lymphocytic leukemia: a study of FILO Group. Clin Pharmacokinet. 2017;56(6):635–47. https://doi.org/10.1007/s40262-016-0470-8.

    Article  CAS  PubMed  Google Scholar 

  4. Tout M, Casasnovas O, Meignan M, et al. Rituximab exposure is influenced by baseline metabolic tumor volume and predicts outcome of DLBCL patients: a Lymphoma Study Association report. Blood. 2017;129(19):2616–23. https://doi.org/10.1182/blood-2016-10-744292.

    Article  CAS  PubMed  Google Scholar 

  5. Regazzi MB, Iacona I, Avanzini MA, et al. Pharmacokinetic behavior of rituximab: a study of different schedules of administration for heterogeneous clinical settings. Ther Drug Monit. 2005;27(6):785–92.

    Article  CAS  Google Scholar 

  6. Muller C, Murawski N, Wiesen MH, et al. The role of sex and weight on rituximab clearance and serum elimination half-life in elderly patients with DLBCL. Blood. 2012;119(14):3276–84. https://doi.org/10.1182/blood-2011-09-380949.

    Article  CAS  PubMed  Google Scholar 

  7. Candelaria M, Gonzalez D, Fernandez Gomez FJ, et al. Comparative assessment of pharmacokinetics, and pharmacodynamics between RTXM83, a rituximab biosimilar, and rituximab in diffuse large B-cell lymphoma patients: a population PK model approach. Cancer Chemother Pharmacol. 2018;81(3):515–27. https://doi.org/10.1007/s00280-018-3524-9.

    Article  CAS  PubMed  Google Scholar 

  8. Blasco H, Chatelut E, de Bretagne IB, Congy-Jolivet N, Le Guellec C. Pharmacokinetics of rituximab associated with CHOP chemotherapy in B-cell non-Hodgkin lymphoma. Fundam Clin Pharmacol. 2009;23(5):601–8. https://doi.org/10.1111/j.1472-8206.2009.00714.x.

    Article  CAS  PubMed  Google Scholar 

  9. Ternant D, Henin E, Cartron G, Tod M, Paintaud G, Girard P. Development of a drug-disease simulation model for rituximab in follicular non-Hodgkin’s lymphoma. Br J Clin Pharmacol. 2009;68(4):561–73. https://doi.org/10.1111/j.1365-2125.2009.03494.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ternant D, Cartron G, Henin E, Tod M, Girard P, Paintaud G. Model-based design of rituximab dosage optimization in follicular non-Hodgkin’s lymphoma. Br J Clin Pharmacol. 2012;73(4):597–605. https://doi.org/10.1111/j.1365-2125.2011.04125.x.

    Article  CAS  PubMed  Google Scholar 

  11. Li J, Zhi J, Wenger M, et al. Population pharmacokinetics of rituximab in patients with chronic lymphocytic leukemia. J Clin Pharmacol. 2012;52(12):1918–26. https://doi.org/10.1177/0091270011430506.

    Article  CAS  PubMed  Google Scholar 

  12. Assouline S, Buccheri V, Delmer A, et al. Pharmacokinetics and safety of subcutaneous rituximab plus fludarabine and cyclophosphamide for patients with chronic lymphocytic leukaemia. Br J Clin Pharmacol. 2015;80(5):1001–9. https://doi.org/10.1111/bcp.12662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lioger B, Edupuganti SR, Mulleman D, et al. Antigenic burden and serum IgG concentrations influence rituximab pharmacokinetics in rheumatoid arthritis patients. Br J Clin Pharmacol. 2017;83(8):1773–81. https://doi.org/10.1111/bcp.13270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ng CM, Bruno R, Combs D, Davies B. Population pharmacokinetics of rituximab (anti-CD20 monoclonal antibody) in rheumatoid arthritis patients during a phase II clinical trial. J Clin Pharmacol. 2005;45(7):792–801. https://doi.org/10.1177/0091270005277075.

    Article  CAS  PubMed  Google Scholar 

  15. Puisset F, White-Koning M, Kamar N, et al. Population pharmacokinetics of rituximab with or without plasmapheresis in kidney patients with antibody-mediated disease. Br J Clin Pharmacol. 2013;76(5):734–40. https://doi.org/10.1111/bcp.12098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gota V, Karanam A, Rath S, et al. Population pharmacokinetics of Reditux, a biosimilar Rituximab, in diffuse large B-cell lymphoma. Cancer Chemother Pharmacol. 2016;78(2):353–9. https://doi.org/10.1007/s00280-016-3083-x.

    Article  CAS  PubMed  Google Scholar 

  17. Dayde D, Ternant D, Ohresser M, et al. Tumor burden influences exposure and response to rituximab: pharmacokinetic-pharmacodynamic modeling using a syngeneic bioluminescent murine model expressing human CD20. Blood. 2009;113(16):3765–72. https://doi.org/10.1182/blood-2008-08-175125.

    Article  CAS  PubMed  Google Scholar 

  18. Ternant D, Monjanel H, Venel Y, et al. Nonlinear pharmacokinetics of rituximab in non-Hodgkin lymphomas: a pilot study. Br J Clin Pharmacol. 2019;85(9):2002–10. https://doi.org/10.1111/bcp.13991.

    Article  CAS  PubMed  Google Scholar 

  19. Ternant D, Bejan-Angoulvant T, Passot C, Mulleman D, Paintaud G. Clinical pharmacokinetics and pharmacodynamics of monoclonal antibodies approved to treat rheumatoid arthritis. Clin Pharmacokinet. 2015;54(11):1107–23. https://doi.org/10.1007/s40262-015-0296-9.

    Article  CAS  PubMed  Google Scholar 

  20. Levy G. Pharmacologic target-mediated drug disposition. Clin Pharmacol Ther. 1994;56(3):248–52.

    Article  CAS  Google Scholar 

  21. Gibiansky L, Gibiansky E. Target-mediated drug disposition model: approximations, identifiability of model parameters and applications to the population pharmacokinetic-pharmacodynamic modeling of biologics. Expert Opin Drug Metab Toxicol. 2009;5(7):803–12. https://doi.org/10.1517/17425250902992901.

    Article  CAS  PubMed  Google Scholar 

  22. Ternant D, Azzopardi N, Raoul W, Bejan-Angoulvant T, Paintaud G. Influence of antigen mass on the pharmacokinetics of therapeutic antibodies in humans. Clin Pharmacokinet. 2019;58(2):169–87. https://doi.org/10.1007/s40262-018-0680-3.

    Article  CAS  PubMed  Google Scholar 

  23. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221–32. https://doi.org/10.1056/NEJMoa0909905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cornec D, Kabat BF, Mills JR, et al. Pharmacokinetics of rituximab and clinical outcomes in patients with anti-neutrophil cytoplasmic antibody associated vasculitis. Rheumatology (Oxford). 2018;57(4):639–50. https://doi.org/10.1093/rheumatology/kex484.

    Article  CAS  Google Scholar 

  25. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1–11. https://doi.org/10.1002/art.37715.

    Article  CAS  PubMed  Google Scholar 

  26. Watts RA, Mahr A, Mohammad AJ, Gatenby P, Basu N, Flores-Suarez LF. Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Nephrol Dial Transpl. 2015;30(Suppl 1):i14–22. https://doi.org/10.1093/ndt/gfv022.

    Article  CAS  Google Scholar 

  27. Mahr A, Guillevin L, Poissonnet M, Ayme S. Prevalences of polyarteritis nodosa, microscopic polyangiitis, Wegener’s granulomatosis, and Churg-Strauss syndrome in a French urban multiethnic population in 2000: a capture-recapture estimate. Arthritis Rheum. 2004;51(1):92–9. https://doi.org/10.1002/art.20077.

    Article  PubMed  Google Scholar 

  28. Cornec D, Cornec-Le Gall E, Fervenza FC, Specks U. ANCA-associated vasculitis—clinical utility of using ANCA specificity to classify patients. Nat Rev Rheumatol. 2016;12(10):570–9. https://doi.org/10.1038/nrrheum.2016.123.

    Article  CAS  PubMed  Google Scholar 

  29. Fussner LA, Hummel AM, Schroeder DR, et al. Factors determining the clinical utility of serial measurements of antineutrophil cytoplasmic antibodies targeting proteinase 3. Arthritis Rheumatol. 2016;68(7):1700–10. https://doi.org/10.1002/art.39637.

    Article  CAS  PubMed  Google Scholar 

  30. Specks UMP, Hoffman GS, Langford CA, Spiera R, Seo P, et al. Design of the Rituximab in ANCA-Associated Vasculitis (RAVE) trial. Open Arthritis J. 2011;4:1–18.

    Article  CAS  Google Scholar 

  31. Mills JR, Cornec D, Dasari S, et al. Using mass spectrometry to quantify rituximab and perform individualized immunoglobulin phenotyping in ANCA-associated vasculitis. Anal Chem. 2016;88(12):6317–25. https://doi.org/10.1021/acs.analchem.6b00544.

    Article  CAS  PubMed  Google Scholar 

  32. Damoiseaux J, Dahnrich C, Rosemann A, et al. A novel enzyme-linked immunosorbent assay using a mixture of human native and recombinant proteinase-3 significantly improves the diagnostic potential for antineutrophil cytoplasmic antibody-associated vasculitis. Ann Rheum Dis. 2009;68(2):228–33. https://doi.org/10.1136/ard.2007.086579.

    Article  CAS  PubMed  Google Scholar 

  33. Specks U, Merkel PA, Seo P, et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med. 2013;369(5):417–27. https://doi.org/10.1056/NEJMoa1213277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wessa P. Free Statistics Software, Office for Research Development and Education, version 1.2.1. 2019. https://www.wessa.net/.

  35. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41. https://doi.org/10.1159/000180580.

    Article  CAS  PubMed  Google Scholar 

  36. Stone JH, Hoffman GS, Merkel PA, et al. International Network for the Study of the Systemic Vasculitides (INSSYS). A disease-specific activity index for Wegener’s granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS). Arthritis Rheum. 2001;44(4):912–20. https://doi.org/10.1002/1529-0131(200104)44:4%3c912:AID-ANR148%3e3.0.CO;2-5.

    Article  CAS  PubMed  Google Scholar 

  37. Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol. 2002;20(24):4713–21. https://doi.org/10.1200/JCO.2002.02.140.

    Article  PubMed  Google Scholar 

  38. van Kesteren C, Zandvliet AS, Karlsson MO, et al. Semi-physiological model describing the hematological toxicity of the anti-cancer agent indisulam. Invest New Drugs. 2005;23(3):225–34. https://doi.org/10.1007/s10637-005-6730-3.

    Article  CAS  PubMed  Google Scholar 

  39. Quartino AL, Friberg LE, Karlsson MO. A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model. Invest New Drugs. 2012;30(2):833–45. https://doi.org/10.1007/s10637-010-9603-3.

    Article  CAS  PubMed  Google Scholar 

  40. Brendel K, Comets E, Laffont C, Mentre F. Evaluation of different tests based on observations for external model evaluation of population analyses. J Pharmacokinet Pharmacodyn. 2010;37(1):49–65. https://doi.org/10.1007/s10928-009-9143-7.

    Article  PubMed  Google Scholar 

  41. RStudio. RStudio: Integrated development environment for R (Version 1.1.383) [Computer software]. Boston, MA; 2015. Retrieved 20 May 2012. Available from http://www.rstudio.org/.

  42. Lavielle M. mlxR: simulation of longitudinal data. R package version 3.2.0. 2017. https://CRAN.R-project.org/package=mlxR.

  43. Melet J, Mulleman D, Goupille P, Ribourtout B, Watier H, Thibault G. Rituximab-induced T cell depletion in patients with rheumatoid arthritis: association with clinical response. Arthritis Rheum. 2013;65(11):2783–90. https://doi.org/10.1002/art.38107.

    Article  CAS  PubMed  Google Scholar 

  44. Amanna IJ, Slifka MK. Mechanisms that determine plasma cell lifespan and the duration of humoral immunity. Immunol Rev. 2010;236:125–38. https://doi.org/10.1111/j.1600-065X.2010.00912.x.

    Article  CAS  PubMed  Google Scholar 

  45. Waldmann TA, Strober W. Metabolism of immunoglobulins. Prog Allergy. 1969;13:1–110.

    CAS  PubMed  Google Scholar 

  46. Scheiermann N, Kuwert EK. Uptake and elimination of hepatitis B immunoglobulins after intramuscular application in man. Dev Biol Stand. 1983;54:347–55.

    CAS  PubMed  Google Scholar 

  47. Thai LH, Charles P, Resche-Rigon M, Desseaux K, Guillevin L. Are anti-proteinase-3 ANCA a useful marker of granulomatosis with polyangiitis (Wegener’s) relapses? Results of a retrospective study on 126 patients. Autoimmun Rev. 2014;13(3):313–8. https://doi.org/10.1016/j.autrev.2013.11.003.

    Article  CAS  PubMed  Google Scholar 

  48. National Institute of Allergy and Infectious Diseases (NIAID). Rituximab for the treatment of Wegener’s granulomatosis and microscopic polyangiitis (RAVE) [ClinicalTrials.gov identifier NCT00104299]. National Institutes of Health, ClinicalTrials.gov. https://clinicaltrials.gov. Accessed 24 Sep 2019.

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Acknowledgements

The authors thank Melissa Cheu, Melissa R. Snyder, Amber M. Hummel, Carol A. Langford, Peter A. Merkel, Paul A. Monach, Philip Seo, Robert F. Spiera, E. William St Clair, Brian F. Kabat, John R. Mills, Darrell R. Schroeder, Matthew D. Cascino, Paul Brunetta, David L. Murray, Fernando Fervenza, and David R. Barnidge for acquiring the data. The authors thank John H. Stone, the principal investigator of the clinical study, for designing the study and acquiring the data.

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Authors and Affiliations

  1. Université de Tours, EA 7501 GICC, Tours, France

    Amina Bensalem, Denis Mulleman, Gilles Paintaud, Nicolas Azzopardi, Valérie Gouilleux-Gruart & David Ternant

  2. Department of Rheumatology, CHRU de Tours, Tours, France

    Denis Mulleman

  3. Department of Medical Pharmacology, CHRU de Tours, Tours, France

    Gilles Paintaud & David Ternant

  4. CNRS, ERL 7001, Tours, France

    Nicolas Azzopardi

  5. Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA

    Divi Cornec & Ulrich Specks

  6. Laboratory of Immunology, CHRU de Tours, Tours, France

    Valérie Gouilleux-Gruart

  7. Rheumatology Department, Brest University Hospital, Brest, France

    Divi Cornec

  8. INSERM U1227, Brest, France

    Divi Cornec

  9. Laboratoire de Pharmacologie-toxicologie, CHRU de Tours, 2 Boulevard Tonnellé, 37044, Tours Cedex, France

    David Ternant

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  1. Amina Bensalem
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Contributions

AB analyzed and interpreted the data, and wrote the manuscript. DM initiated the study, participated in data interpretation, and reviewed the manuscript. US initiated the study, acquired the data, participated in data interpretation, and reviewed the manuscript. VG and GP proposed data investigation methods, participated in data interpretation, and reviewed the manuscript. NA participated in data interpretation and reviewed the manuscript. DC acquired the data, participated in data interpretation, and reviewed the manuscript. DT supervised data analysis and interpretation, manuscript redaction, and reviewed the manuscript.

Corresponding author

Correspondence to David Ternant.

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Funding

The RAVE (Rituximab in ANCA-Associated Vasculitis) trial, from which these data were obtained, was supported by a grant from the National Institute of Allergy and Infectious Diseases to the Immune Tolerance Network (grant N01-AI-15416; protocol no. ITN021AI). Genentech, Inc. and Biogen IDEC, Inc. provided the study medications and partial funding for the trial. Genentech, Inc. performed the rituximab concentration measurements by ELISA for the trial. The ANCA measurements by ELISA were performed at the Mayo Clinic using test kits provided by Euroimmun, Inc. Divi Cornec received fellowship grants from the French Society of Rheumatology and from Brest University Hospital, France. Ulrich Speck’s laboratory is supported by funds from the Connor Group Foundation and the Mayo Foundation. This work was partly supported by the French Higher Education and Research Ministry under the program ‘Investissements d’avenir’ (grant agreement: LabEx MAbImprove ANR-10-LABX-53-01).

Conflict of interest

Amina Bensalem, Nicolas Azzopardi, Valérie Gouilleux-Gruart, Divi Cornec, and Ulrich Specks have no conflicts of interest to declare. Denis Mulleman reports grants from Abbvie and Nordic Pharma, and consultancy fees from MSD, Novartis, UCB, and Pfizer. Gilles Paintaud reports grants received by his research team from Novartis, Roche Pharma, Genzyme, MSD, Chugai, and Pfizer. David Ternant reports lecture fees from Novartis, Amgen, and Boehringer Ingelheim.

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Bensalem, A., Mulleman, D., Paintaud, G. et al. Non-Linear Rituximab Pharmacokinetics and Complex Relationship between Rituximab Concentrations and Anti-Neutrophil Cytoplasmic Antibodies (ANCA) in ANCA-Associated Vasculitis: The RAVE Trial Revisited. Clin Pharmacokinet 59, 519–530 (2020). https://doi.org/10.1007/s40262-019-00826-5

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