A pharmacokinetic comparison of anrukinzumab, an anti‐ IL‐13 monoclonal antibody, among healthy volunteers, asthma and ulcerative colitis patients

Hua, Fei; Ribbing, Jakob; Reinisch, Walter; Cataldi, Fabio; Martin, Steven W.

doi:10.1111/bcp.12589

Cited by 42 publications

(31 citation statements)

References 21 publications

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“…In 7 publications, the type or subtype of disease was associated with differences in pharmacokinetic parameters. [67,70,107,136,[144][145][146] One of possible reasons of such differences are differences in amount and turnover (RT, ksyn, kdeg, see section 4.2), and localization (and therefore the accessibility by mAb) of antigenic targets. The 4 studies of anticancer mAbs that reported different mAb clearances among types of tumour did not investigate pathophysiological reasons of such differences.…”

Section: Influence Of Diseasementioning

confidence: 99%

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: Influence Of Diseasementioning

confidence: 99%

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

et al. 2018

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“…The reasons for this quite “absolute” failure of anti-IL-13 treatment are not easily understood (38). Accelerated clearance of anrukinzumab was reported in UC patients in comparison to healthy volunteers or patients with asthma (39). This implies that a suboptimal dose may have been used in the UC trials.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Role of type 2 immunity in intestinal inflammation

Bamias

Cominelli

2015

Current Opinion in Gastroenterology

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Purpose of Review Type 2 (Th2) immune responses play important roles in intestinal immunity by contributing to the maintenance of mucosal homeostasis, conferring protection against helminthic inflection, but also participating in pro-inflammatory pathways in chronic intestinal inflammatory disorders, including inflammatory bowel disease (IBD). The current review focuses on recent developments regarding the role of type 2 responses in intestinal inflammation. Recent Findings Th2 gut mucosal responses are promoted by mediators that are released following injury to the epithelium and act as alarmin-type danger signals. IL-33 is prominent among such factors and demonstrates a dichotomous function exerting either protective or pro-inflammatory effects, depending on its cellular compartmentalization. The pool of type 2 effector cells has been enriched recently to include not only classical CD4+ Th2 lymphocytes but also a subset of innate lymphocytes (ILC2) that express the transcriptional factor GATA3 and secrete IL-4, IL-5, and IL-13. ILC2 play important roles during infection with helminthes and bi-directionally interact with Th2 CD4+ lymphocytes, thus, establishing a transition from innate to adaptive immunological pathways. Type 2 responses are also involved in pro-inflammatory pathways at the intestinal mucosa and neutralization of the pivotal cytokines IL-4 and IL-13 has been shown to regulate experimental intestinal inflammation. In striking contrast, however, neutralization of human IL-13 had no therapeutic effect in patients with ulcerative colitis. Summary Further studies will be required to delineate the specific mechanisms of type 2 mucosal immunity in IBD and examine the applicability of Th2-targeted therapies for intestinal inflammation.

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“…Because the levels and production of IP-10, as well as its interaction with BMS-986184, may be different in patients with UC compared with healthy participants, dosage projections for patients with UC must be approached with caution. Finally, it should be noted that clearance of mAbs is typically faster in patients with UC than in healthy volunteers, 31,32 and thus consideration must be taken when selecting therapeutic doses for patients.…”

Section: Discussionmentioning

confidence: 99%

Modeling and Simulation of the Pharmacokinetics and Target Engagement of an Antagonist Monoclonal Antibody to Interferon‐γ–Induced Protein 10, BMS‐986184, in Healthy Participants to Guide Therapeutic Dosing

Cai

Leil

Gibiansky³

et al. 2020

Clinical Pharm in Drug Dev

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BMS-986184 is a human, second-generation, anti-interferon-γ-induced protein 10 (IP-10) monoclonal antibody. In this study the pharmacokinetics and target engagement (TE) of BMS-986184 in healthy participants were characterized using population-based target-mediated drug disposition (TMDD) modeling and data from a first-in-human study (NCT02864264). The results of the first-in-human study and the model generated were used to conduct stochastic simulations of a virtual population of healthy participants to predict pharmacokinetic exposures and TE responses for different dosage regimens. A 2-compartment, 2-target, TMDD structural model, assuming quasi-steady-state and stimulated production on treatment, was developed by simultaneous fitting of the total drug, serum-free IP-10, and serum total IP-10 concentration data, with the second unobservable target contribution to drug elimination described by the Michaelis-Menten elimination term. Model evaluation confirmed agreement between model predictions and observed data. Simulation of a virtual population of healthy individuals demonstrated that steady state was reached at the eighth dosing interval, and that around 150 mg subcutaneously every other week could be a suitable target dosage regimen for future clinical trials.Integrated modeling strategies such as this can be used to help guide rational clinical trial development of drugs with TMDD, leading to improved dose selection and greater patient benefits.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Additional supplemental information can be found by clicking the Supplements link in the PDF toolbar or the Supplemental Information section at the end of webbased version of this article.

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A pharmacokinetic comparison of anrukinzumab, an anti‐ IL‐13 monoclonal antibody, among healthy volunteers, asthma and ulcerative colitis patients

Cited by 42 publications

References 21 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

Role of type 2 immunity in intestinal inflammation

Modeling and Simulation of the Pharmacokinetics and Target Engagement of an Antagonist Monoclonal Antibody to Interferon‐γ–Induced Protein 10, BMS‐986184, in Healthy Participants to Guide Therapeutic Dosing

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