Interspecies Scaling in Pharmacokinetics: A Novel Whole-Body Physiologically Based Modeling Framework to Discover Drug Biodistribution Mechanisms in vivo

Hall, Cierra; Lueshen, Eric; Mošat, Andrej; Linninger, Andreas A.

doi:10.1002/jps.22811

Cited by 72 publications

(57 citation statements)

References 51 publications

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“…110 But these scaling laws are critically dependent on the biochemical mechanisms and physical properties of the organs. 111 If the organs do not functionally mimic physiology, they could fail to predict the PK/PD of humans. Differences in drug transport and metabolism in the HoC can render typical allometric PK/PD scaling useless.…”

Section: Examples Of Organ Scalingmentioning

confidence: 99%

Scaling and systems biology for integrating multiple organs-on-a-chip

et al. 2013

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Coupled systems of in vitro microfabricated organs-on-a-chip containing small populations of human cells are being developed to address the formidable pharmacological and physiological gaps between monolayer cell cultures, animal models, and humans that severely limit the speed and efficiency of drug development. These gaps present challenges not only in tissue and microfluidic engineering, but also in systems biology: how does one model, test, and learn about the communication and control of biological systems with individual organs-on-chips that are one-thousandth or one-millionth of the size of adult organs, or even smaller, i.e., organs for a milliHuman (mHu) or microHuman (μHu)? Allometric scaling that describes inter-species variation of organ size and properties provides some guidance, but given the desire to utilize these systems to extend and validate human pharmacokinetic and pharmacodynamic (PK/PD) models in support of drug discovery and development, it is more appropriate to scale each organ functionally to ensure that it makes the suitable physiological contribution to the coupled system. The desire to recapitulate the complex organorgan interactions that result from factors in the blood and lymph places a severe constraint on the total circulating fluid (~5 mL for a mHu and ~5 μL for a μHu) and hence on the pumps, valves, and analytical instruments required to maintain and study these systems. Scaling arguments also provide guidance on the design of a universal cell-culture medium, typically without red blood cells. This review presents several examples of scaling arguments and discusses steps that should ensure the success of this endeavour.

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Section: Examples Of Organ Scalingmentioning

confidence: 99%

Scaling and systems biology for integrating multiple organs-on-a-chip

et al. 2013

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“…It is important to note that, as regards the blood glucose, insulin and glucagon interaction within the human body, the authors did not find other reported results about this interesting task. Although this is a first approach to handle this problem, the proposed method can be extrapolated to other animals (Hall et al, 2012) and also to different case studies. In accordance with Sorensen (1985), this model and the scale up procedure is valid for an average adult healthy human being of 70 kg and an average adult healthy Sprague Dawley rat of 277 g of body weight.…”

Section: Discussionmentioning

confidence: 96%

“…(2) and (3). The organ masses and blood flow rates of rats were taken from the reported data recorded by Hall et al (2012) which can be seen in Table 4, but blood flow rate of the hepatic artery was taken from Daemen et al (1989). Then, with this data, it was possible to estimate the interstitial fluid volumes of Table 3 of about 3.32E −2 l. The final calculation of the physical parameters was done taking into account that the water content of whole blood is roughly 84 volume percent, the blood volumes (Table 2) and flow rates (Table 4) as estimated for a 277 g rat were reduced by 16% for glucose modeling.…”

Section: Physical Parametersmentioning

confidence: 99%

“…For this reason, we considered the first-principles model of Sorensen (1985) because it is the only physiologically based compartmental model which takes into account different parts of the human body such as brain, heart, lungs, liver, gut, kidneys and periphery. Hence, it represents a good starting point to test the scaling procedure recommended in Hall et al (2012) and gives the possibility of being extended to larger problems.…”

Section: Introductionmentioning

confidence: 99%

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A rat–human scale-up procedure for the endocrine system

Campetelli

Lombarte

Biset

et al. 2014

Computers & Chemical Engineering

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“…Between molecular, cellular, patient and population scales, appropriate translations are necessary for evaluating the effects small-scale processes have at large scale and vice-versa (Hall et al, 2011). Deriving patient data directly is not always possible, thus making ex vivo observations and studies imperative.…”

Section: Introductionmentioning

confidence: 99%

A systematic framework for the design, simulation and optimization of personalized healthcare: Making and healing blood

Fuentes-Garí

Velliou

Misener

et al. 2015

Computers & Chemical Engineering

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Highlights(1) The building blocks of a biomedical systems modeling framework are presented (2) Interactions between building blocks are reviewed; two system types are described (3) An example of a laboratory system type is described: artificial blood production (4) An example of a patient system type is discussed: leukemia treatment optimization (5) Other biomedical applications are briefly introduced as part of the framework 2 M. Fuentes-Garí et al. AbstractWe review the key building blocks of a design framework for modeling and optimizing biomedical systems under development in the Biological Systems Engineering Laboratory and the Centre for Process Systems Engineering at Imperial College. The framework features the following components: (i) in vitro environment, where model parameters can be obtained and new setups can be tested; (ii) in silico environment, including a simulation module for representing relevant physical or biological processes, and an optimization module, for calculating of improved in vitro or in vivo outcomes; (iii) in vivo environment, from which organ and patient-specific parameters are collected and which can also implement personalized suggestions for improved outcomes. Two applications in the area of healthy and diseased blood are thoroughly discussed to exemplify the framework's characteristics. We discuss progress in the different areas and the way in which they are connected and finally propose a hybrid in vitro/in silico/in vivo platform. Keywords

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Interspecies Scaling in Pharmacokinetics: A Novel Whole-Body Physiologically Based Modeling Framework to Discover Drug Biodistribution Mechanisms in vivo

Cited by 72 publications

References 51 publications

Scaling and systems biology for integrating multiple organs-on-a-chip

Scaling and systems biology for integrating multiple organs-on-a-chip

A rat–human scale-up procedure for the endocrine system

A systematic framework for the design, simulation and optimization of personalized healthcare: Making and healing blood

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