A physiologically based pharmacokinetic (PBPK) model to characterize and predict the disposition of monoclonal antibody CC49 and its single chain Fv constructs

Davda, Jasmine; Jain, Maneesh; Batra, Surinder K.; Gwilt, Peter R.; Robinson, Dennis H.

doi:10.1016/j.intimp.2007.10.023

Cited by 98 publications

(77 citation statements)

References 24 publications

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“…This would explain the apparent disconnect with previous determinations of the lung partitioning of monoclonal antibodies by physiology-based pharmacokinetics using labeled antibodies in both mice and humans, as these measured interstitial lung tissue measurements. [29][30][31][32][33] This comparison indicates the lung epithelium further limits therapeutic antibody exposure. Conversely, pharmacokinetic studies that uses BAL measurements to quantify partitioning into the lung lumen under-estimate the partitioning due to dilution with the lavage fluid.…”

Section: Discussionmentioning

confidence: 94%

Pulmonary pharmacodynamics of an anti-GM-CSFRα antibody enables therapeutic dosing that limits exposure in the lung

Campbell

Nys

Eghobamien

et al. 2016

mAbs

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Section: Discussionmentioning

confidence: 94%

Pulmonary pharmacodynamics of an anti-GM-CSFRα antibody enables therapeutic dosing that limits exposure in the lung

Campbell

Nys

Eghobamien

et al. 2016

mAbs

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“…Several models (20,22,23,66) have modelled J as the lymphatic flow. However, not all the fluid that drains from (20,21) Multiple compartments with each tissue compartment being divided into vascular and interstitium compartments and endosomal compartment (22)(23)(24)66,69) IgG exchange between vascular and interstitium compartments Diffusive transport Peclet number dependency excluded (20,100) Peclet number dependency included (21,24,25,69) Convective transport J defined as lymphatic flow rate (20,22,23,66) J defined as venous recirculation+lymphatic flow rates (21,24,25,69) FcRn-mediated transcytosis (22)(23)(24)(25)66) IgG elimination First-order process (20,21) FcRn-mediated recycling (22)(23)(24)(25)66,69) arterial capillaries ends up as lymphatic fluid. In a human approximately 0.5% of the plasma flow rate enters tissue interstitium of which the majority is recirculated back at the venous end of capillaries and the remaining (0.07% of blood flow) returns to circulation via lymphatic flow.…”

Section: Large Molecule Pbpk Modelsmentioning

confidence: 99%

“…However a number of PBPK models for large molecules have also been reported (20)(21)(22)(23)(24)(25). In general, these models require large amounts of in vivo tissue distribution data to describe how the large molecule distributes throughout the body.…”

Section: Introductionmentioning

confidence: 99%

Dose Selection Based on Physiologically Based Pharmacokinetic (PBPK) Approaches

Jones

Mayawala

Poulin³

2012

AAPS J

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Abstract. Physiologically based pharmacokinetic (PBPK) models are built using differential equations to describe the physiology/anatomy of different biological systems. Readily available in vitro and in vivo preclinical data can be incorporated into these models to not only estimate pharmacokinetic (PK) parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. They provide a mechanistic framework to understand and extrapolate PK and dose across in vitro and in vivo systems and across different species, populations and disease states. Using small molecule and large molecule examples from the literature and our own company, we have shown how PBPK techniques can be utilised for human PK and dose prediction. Such approaches have the potential to increase efficiency, reduce the need for animal studies, replace clinical trials and increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however some limitations need to be addressed to realise its application and utility more broadly.

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“…A resonating example of mAb PBPK can be seen in the work of Davda et al who constructed a PBPK model for the CC49 mAb to predict not only its biodistribution in various tissues but also in the tumor compartment which was the intended site of action (21). The model gave insights into the factors affecting mAb uptake and accumulation into the tumor tissue.…”

Section: Physiologically Based Pharmacokineticsmentioning

confidence: 99%

Modeling, Simulation, and Translation Framework for the Preclinical Development of Monoclonal Antibodies

Luu

Kraynov

Kuang

et al. 2013

AAPS J

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Abstract. The industry-wide biopharmaceutical (i.e., biologic, biotherapeutic) pipeline has been growing at an astonishing rate over the last decade with the proportion of approved new biological entities to new chemical entities on the rise. As biopharmaceuticals appear to be growing in complexity in terms of their structure and mechanism of action, so are interpretation, analysis, and prediction of their quantitative pharmacology. We present here a modeling and simulation (M&S) framework for the successful preclinical development of monoclonal antibodies (as an illustrative example of biopharmaceuticals) and discuss M&S strategies for its implementation. Critical activities during early discovery, lead optimization, and the selection of starting doses for the first-in-human study are discussed in the context of pharmacokinetic-pharmacodynamic (PKPD) and M&S. It was shown that these stages of preclinical development are and should be reliant on M&S activities including systems biology (SB), systems pharmacology (SP), and translational pharmacology (TP). SB, SP, and TP provide an integrated and rationalized framework for decision making during the preclinical development phase. In addition, they provide increased target and systems understanding, describe and interpret data generated in vitro and in vivo, predict human PKPD, and provide a rationalized approach to designing the first-in-human study.

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A physiologically based pharmacokinetic (PBPK) model to characterize and predict the disposition of monoclonal antibody CC49 and its single chain Fv constructs

Cited by 98 publications

References 24 publications

Pulmonary pharmacodynamics of an anti-GM-CSFRα antibody enables therapeutic dosing that limits exposure in the lung

Pulmonary pharmacodynamics of an anti-GM-CSFRα antibody enables therapeutic dosing that limits exposure in the lung

Dose Selection Based on Physiologically Based Pharmacokinetic (PBPK) Approaches

Modeling, Simulation, and Translation Framework for the Preclinical Development of Monoclonal Antibodies

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