Pharmacokinetic/Pharmacodynamic Modeling of IVIG Effects in a Murine Model of Immune Thrombocytopenia

Deng, Rong; Balthasar, Joseph P.

doi:10.1002/jps.20828

Cited by 23 publications

(21 citation statements)

References 32 publications

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“…13,14 The competition between endogenous IgG and anti-Aβ mIgG2a for FcRn was not considered here due to the low endogenous IgG level (less than 0.1 μg/mL) in SCID mice. 26,27 Based on the work of Garg and Balthasar, 7 the amount of FcRn in each tissue was assumed to be proportional to tissue weight, therefore, the…”

Section: Disclosure Of Potential Conflicts Of Interestmentioning

confidence: 99%

Subcutaneous bioavailability of therapeutic antibodies as a function  of FcRn binding affinity in mice

Deng

Meng

Hoyte

et al. 2012

mAbs

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Section: Disclosure Of Potential Conflicts Of Interestmentioning

confidence: 99%

Subcutaneous bioavailability of therapeutic antibodies as a function  of FcRn binding affinity in mice

Deng

Meng

Hoyte

et al. 2012

mAbs

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“…Several semimechanistic models have been proposed to describe IgG disposition in IVIG setting in experimental animal models [16–19]. These models are discussed in detail in this paper.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Models for FcRn-Mediated IgG Disposition

Xiao¹

2012

Journal of Biomedicine and Biotechnology

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The objectives were to review available PK models for saturable FcRn-mediated IgG disposition, and to explore an alternative semimechanistic model. Most available empirical and mechanistic PK models assumed equal IgG concentrations in plasma and endosome in addition to other model-specific assumptions. These might have led to inappropriate parameter estimates and model interpretations. Some physiologically based PK (PBPK) models included FcRn-mediated IgG recycling. The nature of PBPK models requires borrowing parameter values from literature, and subtle differences in the assumptions may render dramatic changes in parameter estimates related to the IgG recycling kinetics. These models might have been unnecessarily complicated to address FcRn saturation and nonlinear IgG PK especially in the IVIG setting. A simple semimechanistic PK model (cutoff model) was developed that assumed a constant endogenous IgG production rate and a saturable FcRn-binding capacity. The FcRn-binding capacity was defined as MAX, and IgG concentrations exceeding MAX in endosome resulted in lysosomal degradation. The model parameters were estimated using simulated data from previously published models. The cutoff model adequately described the rat and mouse IgG PK data simulated from published models and allowed reasonable estimation of endogenous IgG turnover rates.

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“…Deng et al 77 developed a PK/PD model that links the exposure of an anti-platelet antibody, anti-CD41, to the time-course of platelet counts in a mouse model of sustained ITP. The model combines the effects of intravenous IgG (IVIG) on the clearance of anti-CD41 and platelet counts in anti-CD41-induced ITP mice.…”

Section: Anti-cd41 In Immune Thrombocytopeniamentioning

confidence: 99%

Systems pharmacology and enhanced pharmacodynamic models for understanding antibody-based drug action and toxicity

Ait‐Oudhia¹,

Ovacik²,

Mager³

2016

mAbs

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Pharmacokinetic (PK) and pharmacodynamic (PD) models seek to describe the temporal pattern of drug exposures and their associated pharmacological effects produced at micro-and macro-scales of organization. Antibody-based drugs have been developed for a large variety of diseases, with effects exhibited through a comprehensive range of mechanisms of action. Mechanism-based PK/PD and systems pharmacology models can play a major role in elucidating and integrating complex antibody pharmacological properties, such as nonlinear disposition and dynamical intracellular signaling pathways triggered by ligation to their cognate targets. Such complexities can be addressed through the use of robust computational modeling techniques that have proven powerful tools for pragmatic characterization of experimental data and for theoretical exploration of antibody efficacy and adverse effects. The primary objectives of such multi-scale mathematical models are to generate and test competing hypotheses and to predict clinical outcomes. In this review, relevant systems pharmacology and enhanced PD (ePD) models that are used as predictive tools for antibody-based drug action are reported. Their common conceptual features are highlighted, along with approaches used for modeling preclinical and clinically available data. Key examples illustrate how systems pharmacology and ePD models codify the interplay among complex biology, drug concentrations, and pharmacological effects. New hybrid modeling concepts that bridge cutting-edge systems pharmacology models with established PK/ePD models will be needed to anticipate antibody effects on disease in subpopulations and individual patients. KEYWORDSBoolean network analysis; In vitro cell-based models; In vivo physiologically-based pharmacokinetic models; mechanistic pharmacodynamic models; target mediated drug disposition; translational systems pharmacology

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Pharmacokinetic/Pharmacodynamic Modeling of IVIG Effects in a Murine Model of Immune Thrombocytopenia

Cited by 23 publications

References 32 publications

Subcutaneous bioavailability of therapeutic antibodies as a function  of FcRn binding affinity in mice

Subcutaneous bioavailability of therapeutic antibodies as a function  of FcRn binding affinity in mice

Pharmacokinetic Models for FcRn-Mediated IgG Disposition

Systems pharmacology and enhanced pharmacodynamic models for understanding antibody-based drug action and toxicity

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Pharmacokinetic/Pharmacodynamic Modeling of IVIG Effects in a Murine Model of Immune Thrombocytopenia

Cited by 23 publications

References 32 publications

Subcutaneous bioavailability of therapeutic antibodies as a function of FcRn binding affinity in mice

Subcutaneous bioavailability of therapeutic antibodies as a function of FcRn binding affinity in mice

Pharmacokinetic Models for FcRn-Mediated IgG Disposition

Systems pharmacology and enhanced pharmacodynamic models for understanding antibody-based drug action and toxicity

Contact Info

Product

Resources

About

Subcutaneous bioavailability of therapeutic antibodies as a function  of FcRn binding affinity in mice

Subcutaneous bioavailability of therapeutic antibodies as a function  of FcRn binding affinity in mice