The Influence of Underlying Disease on Rituximab Pharmacokinetics May be Explained by Target-Mediated Drug Disposition.
Journal
Clinical pharmacokinetics
ISSN: 1179-1926
Titre abrégé: Clin Pharmacokinet
Pays: Switzerland
ID NLM: 7606849
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
accepted:
05
10
2021
pubmed:
14
11
2021
medline:
26
4
2022
entrez:
13
11
2021
Statut:
ppublish
Résumé
Rituximab is an anti-CD20 monoclonal antibody approved in several diseases, including chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), rheumatoid arthritis (RA), and anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). The influence of underlying disease on rituximab pharmacokinetics has never been investigated for several cancer and non-cancer diseases simultaneously. This study aimed at assessing this influence using an integrated semi-mechanistic model accounting for target-mediated elimination of rituximab. Rituximab concentration-time data from five studies previously published in patients with CLL, DLBCL, FL, RA, and AAV were described using a two-compartment model with irreversible binding of rituximab to its target antigen. Both underlying disease and target antigen measurements were assessed as covariates. Central volume of distribution was [95% confidence interval] 1.7-fold [1.6-1.9] higher in DLBCL than in RA, FL, and CLL, and it was 1.8-fold [1.6-2.1] higher in RA, FL, and CLL than in AAV. First-order elimination rate constants were 1.8-fold [1.7-2.0] and 1.3-fold [1.2-1.5] higher in RA, DLBCL, and FL than in CLL and AAV, respectively. Baseline latent antigen level (L Our results show for the first time that rituximab pharmacokinetics is strongly influenced by underlying disease and disease activity. Notably, neoplasms are associated with higher antigen amounts that result in decreased exposure to rituximab compared to inflammatory diseases. Our model might be used to estimate unbound target amounts in upcoming studies.
Sections du résumé
BACKGROUND AND OBJECTIVES
Rituximab is an anti-CD20 monoclonal antibody approved in several diseases, including chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), rheumatoid arthritis (RA), and anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). The influence of underlying disease on rituximab pharmacokinetics has never been investigated for several cancer and non-cancer diseases simultaneously. This study aimed at assessing this influence using an integrated semi-mechanistic model accounting for target-mediated elimination of rituximab.
METHODS
Rituximab concentration-time data from five studies previously published in patients with CLL, DLBCL, FL, RA, and AAV were described using a two-compartment model with irreversible binding of rituximab to its target antigen. Both underlying disease and target antigen measurements were assessed as covariates.
RESULTS
Central volume of distribution was [95% confidence interval] 1.7-fold [1.6-1.9] higher in DLBCL than in RA, FL, and CLL, and it was 1.8-fold [1.6-2.1] higher in RA, FL, and CLL than in AAV. First-order elimination rate constants were 1.8-fold [1.7-2.0] and 1.3-fold [1.2-1.5] higher in RA, DLBCL, and FL than in CLL and AAV, respectively. Baseline latent antigen level (L
CONCLUSIONS
Our results show for the first time that rituximab pharmacokinetics is strongly influenced by underlying disease and disease activity. Notably, neoplasms are associated with higher antigen amounts that result in decreased exposure to rituximab compared to inflammatory diseases. Our model might be used to estimate unbound target amounts in upcoming studies.
Identifiants
pubmed: 34773607
doi: 10.1007/s40262-021-01081-3
pii: 10.1007/s40262-021-01081-3
doi:
Substances chimiques
Antigens, CD20
0
Rituximab
4F4X42SYQ6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
423-437Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
Références
Bensalem A, Ternant D. Pharmacokinetic variability of therapeutic antibodies in humans: a comprehensive review of population pharmacokinetic modeling publications. Clin Pharmacokinet. 2020;59(7):857–74.
doi: 10.1007/s40262-020-00874-2
Jing Li ML, Charoin J-E, Frey N, Kheoh T, Ren S, Woo M, 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.
doi: 10.1182/blood.V110.11.2371.2371
Rozman S, Grabnar I, Novakovic S, Mrhar A, Jezersek NB. 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.
doi: 10.1111/bcp.13271
Tout M, Gagez AL, Lepretre S, Gouilleux-Gruart V, Azzopardi N, Delmer A, et al. Influence of FCGR3A-158V/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.
doi: 10.1007/s40262-016-0470-8
Tout M, Casasnovas O, Meignan M, Lamy T, Morschhauser F, Salles G, 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.
doi: 10.1182/blood-2016-10-744292
Regazzi MB, Iacona I, Avanzini MA, Arcaini L, Merlini G, Perfetti V, 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.
doi: 10.1097/01.ftd.0000184162.60197.c1
Muller C, Murawski N, Wiesen MH, Held G, Poeschel V, Zeynalova S, 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.
doi: 10.1182/blood-2011-09-380949
Candelaria M, Gonzalez D, Fernandez Gomez FJ, Paravisini A, Del Campo GA, Perez L, 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.
doi: 10.1007/s00280-018-3524-9
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.
doi: 10.1111/j.1472-8206.2009.00714.x
Li J, Zhi J, Wenger M, Valente N, Dmoszynska A, Robak T, et al. Population pharmacokinetics of rituximab in patients with chronic lymphocytic leukemia. J Clin Pharmacol. 2012;52(12):1918–26.
doi: 10.1177/0091270011430506
Assouline S, Buccheri V, Delmer A, Gaidano G, McIntyre C, Brewster M, 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.
doi: 10.1111/bcp.12662
Lioger B, Edupuganti SR, Mulleman D, Passot C, Desvignes C, Bejan-Angoulvant T, et al. Antigenic burden and serum IgG concentrations influence rituximab pharmacokinetics in rheumatoid arthritis patients. Br J Clin Pharmacol. 2017;83(8):1773–81.
doi: 10.1111/bcp.13270
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.
doi: 10.1177/0091270005277075
Puisset F, White-Koning M, Kamar N, Huart A, Haberer F, Blasco H, 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.
doi: 10.1111/bcp.12098
Gota V, Karanam A, Rath S, Yadav A, Tembhare P, Subramanian P, et al. Population pharmacokinetics of Reditux, a biosimilar rituximab, in diffuse large B-cell lymphoma. Cancer Chemother Pharmacol. 2016;78(2):353–9.
doi: 10.1007/s00280-016-3083-x
Ternant D, Monjanel H, Venel Y, Prunier-Aesch C, Arbion F, Colombat P, et al. Nonlinear pharmacokinetics of rituximab in non-Hodgkin lymphomas: a pilot study. Br J Clin Pharmacol. 2019;85(9):2002–10.
doi: 10.1111/bcp.13991
Lavezzi SM, de Jong J, Neyens M, Cramer P, Demirkan F, Fraser G, et al. Systemic exposure of rituximab increased by ibrutinib: pharmacokinetic results and modeling based on the HELIOS trial. Pharm Res. 2019;36(7):93.
doi: 10.1007/s11095-019-2605-8
Bensalem A, Mulleman D, Thibault G, Azzopardi N, Goupille P, Paintaud G, et al. CD4+ count-dependent concentration-effect relationship of rituximab in rheumatoid arthritis. Br J Clin Pharmacol. 2019;85(12):2747–58.
doi: 10.1111/bcp.14102
Bensalem A, Mulleman D, Paintaud G, Azzopardi N, Gouilleux-Gruart V, Cornec D, 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. 2020;59(4):519–30.
doi: 10.1007/s40262-019-00826-5
Fogueri U, Cheungapasitporn W, Bourne D, Fervenza FC, Joy MS. Rituximab exhibits altered pharmacokinetics in patients with membranous nephropathy. Ann Pharmacother. 2019;53(4):357–63.
doi: 10.1177/1060028018803587
Li J, Levi M, Charoin J, 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.
doi: 10.1182/blood.V110.11.2371.2371
Liu S, Huang H, Chen RX, Wang Z, Guan YP, Peng C, et al. Low initial trough concentration of rituximab is associated with unsatisfactory response of first-line R-CHOP treatment in patients with follicular lymphoma with grade 1/2. Acta Pharmacol Sin. 2021;42:641–7.
doi: 10.1038/s41401-020-0479-2
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.
doi: 10.1007/s40262-018-0680-3
Passot C, Mulleman D, Bejan-Angoulvant T, Aubourg A, Willot S, Lecomte T, et al. The underlying inflammatory chronic disease influences infliximab pharmacokinetics. MAbs. 2016;8(7):1407–16.
doi: 10.1080/19420862.2016.1216741
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.
doi: 10.2174/1876539401104010001
Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221–32.
doi: 10.1056/NEJMoa0909905
Blasco H, Lalmanach G, Godat E, Maurel MC, Canepa S, Belghazi M, et al. Evaluation of a peptide ELISA for the detection of rituximab in serum. J Immunol Methods. 2007;325(1–2):127–39.
doi: 10.1016/j.jim.2007.06.011
Mills JR, Cornec D, Dasari S, Ladwig PM, Hummel AM, Cheu M, et al. Using mass spectrometry to quantify rituximab and perform individualized immunoglobulin phenotyping in ANCA-associated vasculitis. Anal Chem. 2016;88(12):6317–25.
doi: 10.1021/acs.analchem.6b00544
Pearson TC, Guthrie DL, Simpson J, Chinn S, Barosi G, Ferrant A, et al. Interpretation of measured red cell mass and plasma volume in adults: expert panel on Radionuclides of the International Council for Standardization in Haematology. Br J Haematol. 1995;89(4):748–56.
doi: 10.1111/j.1365-2141.1995.tb08411.x
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.
doi: 10.1002/art.38107
Cornec D, Kabat BF, Mills JR, Cheu M, Hummel AM, Schroeder DR, et al. Pharmacokinetics of rituximab and clinical outcomes in patients with anti-neutrophil cytoplasmic antibody associated vasculitis. Rheumatology (Oxford). 2018;57(4):639–50.
doi: 10.1093/rheumatology/kex484
Boellaard R, Delgado-Bolton R, Oyen WJ, Giammarile F, Tatsch K, Eschner W, et al. FDG PET/CT: EANM procedure guidelines for tumour imaging: version 20. Eur J Nucl Med Mol Imaging. 2015;42(2):328–54.
doi: 10.1007/s00259-014-2961-x
Meignan M, Sasanelli M, Casasnovas RO, Luminari S, Fioroni F, Coriani C, et al. Metabolic tumour volumes measured at staging in lymphoma: methodological evaluation on phantom experiments and patients. Eur J Nucl Med Mol Imaging. 2014;41(6):1113–22.
doi: 10.1007/s00259-014-2705-y
Savic RM, Karlsson MO. Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions. AAPS J. 2009;11(3):558–69.
doi: 10.1208/s12248-009-9133-0
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.
doi: 10.1007/s10928-009-9143-7
RStudio Team. RStudio: integrated development for R. 2015. Boston: RStudio, Inc. http://www.rstudio.com/ . Accessed 13 Oct 2021.
Marc Lavielle. mlxR: simulation of longitudinal data. R package version 4.1.0. 2017. https://CRAN.R-project.org/package=mlxR . Accessed 13 Oct 2021.
Dartigeas C, Van Den Neste E, Leger J, Maisonneuve H, Berthou C, Dilhuydy MS, et al. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study. Lancet Haematol. 2018;5(2):e82-94.
doi: 10.1016/S2352-3026(17)30235-1
Dai HI, Vugmeyster Y, Mangal N. Characterizing exposure-response relationship for therapeutic monoclonal antibodies in immuno-oncology and beyond: challenges, perspectives, and prospects. Clin Pharmacol Ther. 2020;108(6):1156–70.
doi: 10.1002/cpt.1953
Le Louedec F, Alix-Panabieres C, Lafont T, Allal BC, Garrel R, Digue L, et al. Cetuximab pharmacokinetic/pharmacodynamics relationships in advanced head and neck carcinoma patients. Br J Clin Pharmacol. 2019;85(6):1357–66.
doi: 10.1111/bcp.13907
Le Louedec F, Chatelut E. Correlation between bevacizumab exposure and survival does not necessarily imply causality. Oncologist. 2020;25(12):e2022.
doi: 10.1002/onco.13564
Lamy T, Damaj G, Soubeyran P, Gyan E, Cartron G, Bouabdallah K, et al. R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood. 2018;131(2):174–81.
doi: 10.1182/blood-2017-07-793984