Bevacizumab Pharmacokinetics Influence Overall and Progression-Free Survival in Metastatic Colorectal Cancer Patients

Caulet, Morgane; Lecomte, Thierry; Bouché, Olivier; Rollin, Jérôme; Gouilleux-Gruart, Valérie; Azzopardi, Nicolas; Léger, Julie; Borg, Christophe; Douillard, Jean-Yves; Manfrédi, Sylvain; Smith, Denis; Capitain, Olivier; Ferru, Aurélie; Moussata, Driffa; Terrebone, Eric; Paintaud, Gilles; Ternant, David

doi:10.1007/s40262-016-0406-3

Cited by 48 publications

(54 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Among the 85 publications which reported an influence of antigen mass, 29 reported an influence of a covariate related to antigen mass on pharmacokinetic parameters (table 1). 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.…”

Section: Antigen Mass As a Covariate Of Pharmacokinetic Parametersmentioning

confidence: 99%

“…Since techniques of tumor size measurements and their target-antigen density are very different between type of cancer, it is difficult to deliver a global message on the influence of tumor size on mAb pharmacokinetics, even if 7 publications reported and increase in mAb clearance with pre-therapeutic tumour size (table 1): -breast cancer size for trastuzumab [94] and trastuzumab emtansine [131,133] ; -bladder urothelial carcinoma size for atezolizumab [134] ; -size of various solid tumors for olaratumumab [135] and pembrolizumab [136] ; -and the number of extrahepatic metastases for bevacizumab [130] .…”

Section: Influence Of Tumor Sizementioning

confidence: 99%

“…Eight publications reported an increase in mAb clearance with pretherapeutic levels of a biomarker ( Figure 3, table 1): -Lymphocyte counts for efalizumab [92] , even if the link between CD11a expression and total lymphocyte count may be considered as very indirect; -Carcino-embryonic antigen (CEA) concentration for bevacizumab [130] is indirectly related to tumour burden but not with VEGF concentrations (see section 5.2);…”

Section: Influence Of Biomarkersmentioning

confidence: 99%

“…[4] Elimination half-life (T½R) estimates of bevacizumab was 21 days in teleangiectasia [147] , 17-20 days in various solid tumours [148,149] , 15-17 days in child sarcoma [144,150] , and 19 days in colorectal cancer (CRC) and, surprisingly, 44 days in multi-metastatic CRC. [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).…”

Section: Influence Of Diseasementioning

confidence: 99%

“…Increased bevacizumab clearance was associated with pre-therapeutic VEGF and ACE serum concentrations, and the number of extrahepatic metastases. [130] The circulating VEGF is only a part of total VEGF available for bevacizumab binding. Being higher inside the tumor and in the microenvironment [168] , total VEGF burden should increase with tumour size and number of metastases.…”

Section: Antigenic Targets Present In Several Tissuesmentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2018

Self Cite

View full text Add to dashboard Cite

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

show abstract

Section: Antigen Mass As a Covariate Of Pharmacokinetic Parametersmentioning

confidence: 99%

Section: Influence Of Tumor Sizementioning

confidence: 99%

Section: Influence Of Biomarkersmentioning

confidence: 99%

Section: Influence Of Diseasementioning

confidence: 99%

Section: Antigenic Targets Present In Several Tissuesmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

Towards Rational Cancer Therapeutics: Optimizing Dosing, Delivery, Scheduling, and Combinations

Ferrer

Fanciullino

Milano

et al. 2020

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

The current trend to personalize anticancer therapies mostly relies on selecting the best drug or combination of drugs to achieve optimal efficacy in patients. In addition to the comprehensive genetic and molecular knowledge of each tumor before choosing the drugs to be given, there is probably much room left for improvement by further personalizing the very modes by which the drugs are given, once they have been carefully selected. In particular, shifting from standard dosing to tailored dosing should help in maintaining drug exposure levels in the right therapeutic window, thus ensuring that the efficacy/toxicity balance is optimal. This paper covers the current knowledge regarding pharmacokinetic/pharmacodynamic relationships of anticancer agents, from decades‐old cytotoxics to the latest immune checkpoint inhibitors, the most frequent sources for long‐neglected interpatient variability impacting on drug exposure levels, and what could be done to achieve real personalized medicine in oncology such as implementing therapeutic drug monitoring with adaptive dosing strategies or using model‐driven modalities for personalized dosing and scheduling.

show abstract

Correlation Between Bevacizumab Exposure and Survival Does Not Necessarily Imply Causality

Louedec

Chatelut

2020

The Oncologist

View full text Add to dashboard Cite

Papachristos et al. [1] found that patients with metastatic colorectal cancer and plasma bevacizumab trough concentrations ≤41.9 mg/L in cycles 2-4 had a lower probability of surviving, as previously reported [2]. They suggested that underexposed patients could benefit from therapeutic drug monitoring (TDM) followed by dose increase. However, this pharmacokinetics (PK)/pharmacodynamics relationship is probably misinterpreted. As for other monoclonal antibodies (mAbs), higher clearance (CL) of bevacizumab has been observed in patients with cachexia with poor World Health Organization performance status (PS) [3] or hypoalbuminemia [4]. Thus, the correlation herein reported between PK and survival is likely due to disease stage as a confounding factor. This was previously reported by Turner et al., who showed that regardless of whether patients were treated by 2 or 10 mg/kg of pembrolizumab, the stratified-by-CL Kaplan-Meier survival curves perfectly overlaid despite a mean fivefold difference in exposure between the two dose levels [5]. To confirm these hypotheses, the authors of the current paper could check whether patients with poor PS at inclusion have lower early bevacizumab concentrations. They could also include PS in a multivariate Cox analysis to see if bevacizumab concentrations remain a significant variable (as was done for cetuximab data [6]). Moreover, mAbs CL was shown to decrease over time in patients with better outcomes, consistent with reversion of cachexia [7]. In the current paper, the authors did not report data on PK intraindividual variability, whereas drug concentrations were measured up to cycle 30. They could look for a trend in higher bevacizumab accumulation in patients with improving disease status. Overall, due to these noncausal exposure/response relationships, the benefit of mAbs TDM in improving efficacy is not demonstrated. Indeed, there is as yet no evidence that an increased dose in underexposed patients would be associated with improved outcome.

show abstract

Bevacizumab Pharmacokinetics Influence Overall and Progression-Free Survival in Metastatic Colorectal Cancer Patients

Abstract: High tumour burden is associated with low bevacizumab concentrations, and high bevacizumab concentration are associated with both decreased overall and progression-free survivals.

Cited by 48 publications

References 37 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

Towards Rational Cancer Therapeutics: Optimizing Dosing, Delivery, Scheduling, and Combinations

Correlation Between Bevacizumab Exposure and Survival Does Not Necessarily Imply Causality

Contact Info

Product

Resources

About