Antigenic burden and serum IgG concentrations influence rituximab pharmacokinetics in rheumatoid arthritis patients

Lioger, Bertrand; Edupuganti, Soujanya Ratna; Mulleman, Denis; Passot, Christophe; Desvignes, Céline; Bejan-Angoulvant, Théodora; Thibault, Gilles; Gouilleux-Gruart, Valérie; Melet, J; Paintaud, Gilles; Ternant, David

doi:10.1111/bcp.13270

Cited by 27 publications

(32 citation statements)

References 31 publications

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“…Rituximab showed nonlinear pharmacokinetics for chronic lymphocytic leukemia (CLL) [52,90] but not for other B-cell malignancies [96][97][98] or RA. [99,100] For some of them, as anti-TNF mAbs, nonlinearity was never observed in 26 publications, with infliximab [101][102][103][104][105][106][107][108][109][110][111][112][113][114] , adalimumab [115][116][117][118][119][120][121][122] , certolizumab pegol [123,124] and golimumab. [125][126][127][128] This may be due to an excess of anti-TNF mAbs compared to TNF-α concentrations.…”

Section: Antigen Mass As a Covariate On Target-mediated Elimination Pmentioning

confidence: 99%

“…Among these, pre-therapeutic measurements of circulating antigenic targets were found to be associated with pharmacokinetic parameters in 5 publications: -VEGF-A concentration for bevacizumab [130] ; -extracellular domain of HER2 for trastuzumab [95] and trastuzumab emtansine [131] ; -complement component 5 (C5) for eculizumab [132] ; -CD19+ (B-cell) counts for rituximab. [99] Concentrations of circulating antigenic targets, when available, show consistently an influence of antigen burden on mAb pharmacokinetics. However, circulating targets may not be fully sensitive, i.e.…”

Section: Antigen Mass As a Covariate Of Pharmacokinetic Parametersmentioning

confidence: 99%

“…[130] For trastuzumab, T½R was 28 days in metastatic breast cancer (BC), but highly controversial in early BC, 12 days [94] or 40 days. [69] The pharmacokinetics of rituximab is highly variable between diseases: T½R is approximately 20 days in follicular non-Hodgkin lymphoma [97] and in RA [49,99] and 40-100 days in diffuse large B cell lymphoma (DLBCL). [96,98,151].…”

Section: Influence Of Diseasementioning

confidence: 99%

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Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

et al. 2018

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Therapeutic antibodies are increasingly used to treat various diseases, including neoplasms and chronic inflammatory diseases. Antibodies exhibit complex pharmacokinetic properties, notably due to the influence of antigen mass, i.e. the amount of antigenic targets to which the monoclonal antibody binds specifically. This review focuses on the influence of antigen mass on the pharmacokinetics of therapeutic antibodies quantified by pharmacokinetic modelling in humans. Out of 159 pharmacokinetic studies, 85 reported an influence of antigen mass. This influence led to nonlinear elimination decay in 50 publications which was described using target-mediated drug disposition (TMDD) or derived models, as quasi-steady-state, irreversible binding and Michaelis-Menten models. In 35 publications, the pharmacokinetics was apparently linear and the influence of antigen mass was described as covariate of pharmacokinetic parameters. If some reported covariates, such as circulating antigen concentration or tumor size, are likely to be correlated to antigen mass, others, such as disease activity or disease type, may contain little information on the amount of antigenic targets. In some cases, antigen targets exist in different forms, notably in the circulation and expressed at cell surface. The influence of antigen mass should be soundly described during the early clinical phases of drug development. To maximize therapeutic efficacy, sufficient antibody doses should be administered to ensure the saturation of antigen targets by therapeutic antibody in all patients. If necessary, antigen mass should be taken into account in routine clinical practice. Key points-Current knowledge on the pharmacokinetics of monoclonal antibodies (mAbs) states that higher antigen amount was associated with mAb concentrations and higher mAb clearance. -Beacause of antigen mass, mAb pharmacokinetics may display nonlinear elimination shape. The influence of antigen mass on mAb pharmacokinetics is described using target-mediated drug disposition (TMDD) model, or approximations of this model. Antigen mass influence may be quantified using covariates. -Current mAb clinical development and use in clinical practice may be improved by optimization of dose, which should ensure the saturation of antigen targets in all patients.3

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Section: Antigen Mass As a Covariate On Target-mediated Elimination Pmentioning

confidence: 99%

Section: Antigen Mass As a Covariate Of Pharmacokinetic Parametersmentioning

confidence: 99%

Section: Influence Of Diseasementioning

confidence: 99%

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Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

et al. 2018

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“…Rituximab, a chimaeric IgG1 therapeutic monoclonal antibody binding CD20 antigen, is approved in 2 B‐cell malignancies, non‐Hodgkin lymphomas (NHL) and chronic lymphocytic leukaemia (CLL). The pharmacokinetics of rituximab were described in 12 pharmacokinetic modelling studies in NHL, CLL and rheumatoid arthritis . and in patients under plasmapherisis .…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, higher CD20 expression in CLL, larger metabolic tumour volume (MTV) in lymphomas and higher CD19+ count in rheumatoid arthritis were associated with lower rituximab concentrations. Rituximab pharmacokinetics were reported to be linear in lymphomas and rheumatoid arthritis, despite the influence of antigen mass on either rituximab clearance or volume of distribution . Nonlinear pharmacokinetics were reported in a murine model of lymphoma expressing human CD20, where rituximab clearance increased with tumour volume .…”

Section: Introductionmentioning

confidence: 99%

Nonlinear pharmacokinetics of rituximab in non‐Hodgkin lymphomas: A pilot study

Ternant

Monjanel

Venel

et al. 2019

Brit J Clinical Pharma

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Aims Rituximab is an anti‐CD20 monoclonal antibody approved in non‐Hodgkin lymphoma (NHL). This study aimed to assess the relationship between antigen mass and nonlinear pharmacokinetics of rituximab in NHL patients. Methods In a retrospective cohort of 25 NHL patients treated with rituximab, antigen mass was assessed at baseline by measuring metabolic tumour volume (MTV) by positron emission tomography. Rituximab pharmacokinetics was described using a semimechanistic 2‐compartment model including a latent target antigen. Rituximab target‐mediated elimination was described as irreversible binding between rituximab and it target. Histology (follicular or diffuse large B‐cell lymphomas), initial MTV and body weight were tested as covariates on pharmacokinetic parameters. Results The model allowed a satisfactory description of rituximab serum concentrations. Target‐mediated elimination was maximum at the beginning of treatment and became negligible towards the end of follow‐up. The second‐order elimination of rituximab due to target binding and complex elimination increased with baseline MTV. Central volume of distribution increased with body weight (P = .022) and baseline MTV (P = .005). Conclusions This study quantified for the first time the target‐mediated elimination of rituximab in NHL patients and confirmed rituximab retention by antigen mass.

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Population pharmacokinetics and exposure–response relationship of trastuzumab and bevacizumab in early-stage breast cancer

Petitcollin

Azzopardi

Pierga

et al. 2021

Eur J Clin Pharmacol

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Antigenic burden and serum IgG concentrations influence rituximab pharmacokinetics in rheumatoid arthritis patients

Cited by 27 publications

References 31 publications

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

Nonlinear pharmacokinetics of rituximab in non‐Hodgkin lymphomas: A pilot study

Population pharmacokinetics and exposure–response relationship of trastuzumab and bevacizumab in early-stage breast cancer

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