Monoclonal antibody disposition: a simplified PBPK model and its implications for the derivation and interpretation of classical compartment models

Fronton, Ludivine; Pilari, Sabine; Huisinga, Wilhelm

doi:10.1007/s10928-014-9349-1

Cited by 38 publications

(34 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because, theoretically, all chimeric, humanized and human monoclonal antibodies are similar to endogenous IgG, important differences are observed between antibodies and diseases, which are due, at least in part, to target antigen mass. Structural pharmacokinetic model describing antibodies is bicompartimental [6,171], and target-mediated drug disposition (TMDD) models are used to describe antibody and target joint kinetics.…”

Section: Antigenic Targets Present In Several Tissuesmentioning

confidence: 99%

“…[1][2][3][4][5] The pharmacokinetics of mAbs is usually described using 2-compartment models with first-order transfer rates. [6] Central and steady-state volumes of distribution of mAbs are usually 3-5 L and 5-15 L [1,2,4] , respectively, values which suggest that mAbs are confined to lymphatic and blood vessels, and exhibit low (but not inexistent) tissue penetration. The elimination of IgG involves two different pathways.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2018

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: Antigenic Targets Present In Several Tissuesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The influence of target antigenic mass is described in Sect. 3.2.2 [28]. More specifically, two-compartment models were used to describe the pharmacokinetics of infliximab [29], rituximab [30], adalimumab [31,32], golimumab [33], and tocilizumab in RA [34,35].…”

Section: Pharmacokinetics Of Mabs Used In Ramentioning

confidence: 99%

“…Therefore, the common interpretation for IgG low volumes of distribution being essentially confined inside blood and interstitial tissues may be abusive. Indeed, a recent study used physiologically based pharmacokinetics and suggested that, central and peripheral compartments of twocompartment models may not be considered as blood and interstitial spaces, respectively, but rather as two distinct groups of tissues, some being kinetically similar to plasma and others not [28]. In addition, non-specific elimination may concern not only unbound antibodies, but also antibody-target complexes.…”

Section: Distributionmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis

et al. 2015

View full text Add to dashboard Cite

Monoclonal antibodies (mAbs) are increasingly used to treat rheumatoid arthritis (RA). At present, anti-tumor necrosis factor-α drugs (infliximab, adalimumab, certolizumab pegol, and golimumab), rituximab, and tocilizumab are approved for RA treatment. This review focuses on the pharmacokinetics and pharmacodynamics of mAbs approved in RA. Being large proteins, mAbs exhibit complex pharmacokinetic and pharmacodynamic properties. In particular, owing to the interactions of mAbs with their antigenic targets, the pharmacokinetics of mAbs depends on target turnover and exhibits non-specific (linear) and target-mediated (often nonlinear) clearances. Their volume of distribution is low (3-4 L) and their elimination half-life usually ranges from 2 to 3 weeks. The inter-individual pharmacokinetic variability of mAbs is usually large and is partly explained by differences in antigenic burden or by anti-drug antibodies, which accelerate mAb elimination. The inter-individual variability of clinical response is large and influenced by the pharmacokinetics. The analysis of mAbs concentration-effect relationship relies more and more often on pharmacokinetic-pharmacodynamic modeling; these models being suitable for dosing optimization. Even if adverse effects of mAbs used in RA are well known, the relationship between mAb concentration and adverse effects is poorly documented, especially for anti-tumor necrosis factor-α mAbs. Overall, RA patients treated with mAbs should benefit from individualized dosing strategies. Because of the complexity of their pharmacokinetics and mechanisms of action, the current dosing strategy of mAbs is not based on sound knowledge. New studies are needed to assess individual dosing regimen, adjusted notably to disease activity.

show abstract

“…The concept of minimal PBPK models is not novel and "hybrid PBPK models" (13,14) or minimal PBPK models (12) have been used to describe the disposition of small chemical molecules. These concepts have been recently extended to the modelling of mAbs for mice (15) and for both mice and humans (12,16), but FcRn-mediated distribution and elimination are not explicitly taken account of in these minimal versions of PBPK model for mAbs.…”

Section: Introductionmentioning

confidence: 99%

Simulation of Monoclonal Antibody Pharmacokinetics in HumansUsing a Minimal Physiologically Based Model

Gardner

Dostálek

et al. 2014

AAPS J

View full text Add to dashboard Cite

Abstract. Compared to small chemical molecules, monoclonal antibodies and Fc-containing derivatives (mAbs) have unique pharmacokinetic behaviour characterised by relatively poor cellular permeability, minimal renal filtration, binding to FcRn, target-mediated drug disposition, and disposition via lymph. A minimal physiologically based pharmacokinetic (PBPK) model to describe the pharmacokinetics of mAbs in humans was developed. Within the model, the body is divided into three physiological compartments; plasma, a single tissue compartment and lymph. The tissue compartment is further subdivided into vascular, endothelial and interstitial spaces. The model simultaneously describes the levels of endogenous IgG and exogenous mAbs in each compartment and sub-compartment and, in particular, considers the competition of these two species for FcRn binding in the endothelial space. A Monte-Carlo sampling approach is used to simulate the concentrations of endogenous IgG and mAb in a human population. Existing targeted-mediated drug disposition (TMDD) models are coupled with the minimal PBPK model to provide a general platform for simulating the pharmacokinetics of therapeutic antibodies using primarily pre-clinical data inputs. The feasibility of utilising pre-clinical data to parameterise the model and to simulate the pharmacokinetics of adalimumab and an anti-ALK1 antibody (PF-03446962) in a population of individuals was investigated and results were compared to published clinical data.

show abstract

Monoclonal antibody disposition: a simplified PBPK model and its implications for the derivation and interpretation of classical compartment models

Cited by 38 publications

References 35 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

Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis

Simulation of Monoclonal Antibody Pharmacokinetics in HumansUsing a Minimal Physiologically Based Model

Contact Info

Product

Resources

About