Potential Sources of Inter-Subject Variability in Monoclonal Antibody Pharmacokinetics

Gill, Katherine L.; Machavaram, Krishna K.; Rose, Rachel H.; Chetty, Manoranjenni

doi:10.1007/s40262-015-0361-4

Cited by 66 publications

(57 citation statements)

References 169 publications

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“…BW was a key covariate identified in this analysis for both CL and VC for all screened mAbs used in oncology. Although the effect of BW on the PK of mAbs is well established, we have shown here that both CL and VC increased with an increase in BW, and the magnitude of the effect of BW for respective PK parameters was similar across the majority of mAbs analysed. It is also notable that the magnitude of effect of BW on CL was substantially higher for elotuzumab, rituximab and trastuzumab when compared with other mAbs.…”

Section: Discussionmentioning

confidence: 96%

“…BW‐based dosing has traditionally been used in the development of therapeutic mAbs, as body size was believed to account for a major source of variability across individuals . This is supported by the argument that larger individuals have a higher volume of distribution due to a greater volume of plasma and interstitial fluid when compared with smaller individuals, and that there is lower linear elimination in smaller compared with larger individuals . Considering that BW has a significant effect on CL and VC, it may seem logical to use BW‐based dosing with mAbs compared with flat dosing.…”

Section: Discussionmentioning

confidence: 99%

“…In this approach, the PK of a mAb is characterized in the target patient population and IIV is investigated by assessing the effect of different covariates on PK parameters, including CL and volume of distribution (central and peripheral). Historically, the commonly tested covariates in PopPK models include body size (weight or surface area), sex, ethnicity and age . However, the influence of other demographic factors, disease status and comorbidities, immunogenicity status (defined by the presence or absence of antidrug antibodies), blood chemistry parameters, and concomitant medications is also often assessed .…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology

Bajaj

Suryawanshi

Roy

et al. 2019

Brit J Clinical Pharma

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Aims The development of monoclonal antibodies (mAbs) requires an understanding of the interindividual variability (IIV) in pharmacokinetics (PK) at the population level facilitated by population PK (PopPK) modelling. However, there is no clear rationale for selecting which covariates to screen during PopPK model development. Here, we compare the effect of covariates on PK parameters for mAbs in oncology and identify the most commonly used covariates affecting PK parameters. Methods All 25 mAbs approved for therapeutic use in oncology until December 2017 by the Food and Drug Administration and the European Medicines Agency were selected for study. Literature searches revealed 23 available PopPK models for these mAbs. To understand the magnitude and types of covariate effect on PK parameters, all covariates included in the final PopPK model for each mAb were summarized. Results The most commonly identified covariates were baseline body weight (BW; 17 mAbs), baseline serum albumin (8 mAbs), and sex (7 mAbs) on clearance; and BW (16 mAbs) and sex (12 mAbs) on central volume of distribution. A reduced PopPK model was developed for nivolumab and ipilimumab using these covariates, and the percentage of explained IIV from the reduced model (20.3% and 16.8%, respectively) was compared with that from the full model (24.5% and 27.9%, respectively). Conclusions This analysis provides a uniform platform for selecting covariates and suggests that the effect of BW, albumin and sex should be included during the development of PopPK models for mAbs in oncology. The reduced model was able to explain IIV to a similar extent as the full model.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology

Bajaj

Suryawanshi

Roy

et al. 2019

Brit J Clinical Pharma

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“…Many other factors, such as antibody properties (hydrophobicity, charge, glycosylation patterns), intersubject variability (disease status, body size, genetic polymorphisms, concomitant medication, comorbidities, etc …”

Section: Metabolism/catabolism and Clearance Mechanisms Of Mabsmentioning

confidence: 99%

Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development

Ovacik¹,

Lin

2018

Clinical Translational Sci

207

154

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The tutorial introduces the readers to the fundamentals of antibody pharmacokinetics (PK) in the context of drug development. Topics covered include an overview of antibody development, PK characteristics, and the application of antibody PK/pharmacodynamics (PD) in research and development decision‐making. We also discuss the general considerations for planning a nonclinical PK program and describe the types of PK studies that should be performed during early development of monoclonal antibodies.

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“…[1-5, [7][8][9][10][11][12][13] The pharmacokinetic variability of mAbs may be explained by several individual factors. The most frequent are: -An increase in volume of distribution and clearance with body size, as measured by body weight, height or fat-free mass); Higher volume of distribution and clearance in male than in female; -An increase in clearance when serum albumin decreases; -A dramatical increase in mAb clearance when anti-drug antibodies are present, leading to low mAb concentrations and hence loss of response.…”

Section: Introductionmentioning

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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Potential Sources of Inter-Subject Variability in Monoclonal Antibody Pharmacokinetics

Cited by 66 publications

References 169 publications

Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology

Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology

Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development

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

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