Open AccessJournal Article
Biodistribution of monoclonal antibodies: scale-up from mouse to human using a physiologically based pharmacokinetic model.
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TLDR
A physiologically based pharmacokinetic model for scaling up data from mice to humans, the first such model for genetically engineered macromolecules that bind to their targets in vivo, such as mAbs, was developed.Abstract:
The efficacy of a novel diagnostic or therapeutic agent depends on its selective localization in a target tissue. Biodistribution studies are expensive and difficult to carry out in humans, but such data can be obtained easily in rodents. We have developed a physiologically based pharmacokinetic model for scaling up data from mice to humans, the first such model for genetically engineered macromolecules that bind to their targets in vivo, such as mAbs. The mathematical model uses physiological parameters including organ volumes, blood flow rates, and vascular permeabilities; the compartments (organs) are connected anatomically. This allows the use of scale-up techniques to predict antibody distribution in humans. The model was tested with data obtained in human patients for the biodistribution of a mAb against carcinoembryonic antigen. The model was further tested for a two-step protocol: bifunctional antibodies and radiolabeled hapten, which compared favorably with data in both mice and humans. The model was useful for optimization of treatment parameters, such as dose and time interval of injections, binding affinities, and choice of molecular carrier. This framework may be applicable to other genetically engineered molecules (e.g., growth factors, antisense oligonucleotides, and gene-carrying vectors).read more
Citations
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References
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Book
Textbook of Medical Physiology
Arthur C. Guyton,John E. Hall +1 more
TL;DR: Textbook of medical physiology , Textbook ofmedical physiology , کتابخانه دیجیتال جندی شاپور اهواز
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Textbook of Medical Physiology
TL;DR: Textbook of medical physiology, Textbook of Medical Physiology, this paper, textbook of medicine, textbooks of medical science, text book of medical literature, textbook medical physiology.
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Fan Yuan,Marc Dellian,Dai Fukumura,Michael Leunig,David A. Berk,Vladimir P. Torchilin,Rakesh K. Jain +6 more
TL;DR: Tumor vessels in the model found that tumor vessels in this model were permeable to liposomes of up to 400 nm in diameter, suggesting that the cutoff size of the pores is between 400 and 600nm in diameter.
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Transport of molecules across tumor vasculature.
TL;DR: The vascular-extravascular exchange of fluid and solute molecules in a tissue is determined by the transport parameters, which have significant implications in tumor growth, metastasis, detection and treatment.
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LSODE and LSODI, two new initial value ordinary differential equation solvers
TL;DR: Two new packages are available for the numerical solution of the initial value problem for stiff and nonstiff systems of ordinary differential equations (ODE's). LSODE solves explicitly given ODE systems, while LSODI solves systems given in linearly implicit form, including differential-algebraic systems.