Multiphysics Modeling and Simulation of Subcutaneous Injection and Absorption of Biotherapeutics: Model Development

Zheng, Fudan; Hou, Peng; Corpstein, Clairissa D.; Lü, Xing; Li, Tonglei

doi:10.1007/s11095-021-03032-w

Cited by 19 publications

(3 citation statements)

References 89 publications

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“…The main gap is to be able to predict tissue backpressure with highly viscous solutions or solutions which have non-Newtonian viscous behaviour. For example, this work could benefit from the multiphysics model introduced by Zheng et al [ 63 ] and Hou et al [ 64 ] to gain additional mechanistic insights into fluid flow through tissue as well as the impact of viscosity and mechanical interlocking of hyaluronan. This latter point will greatly benefit from a more mechanistic fluid flow model since the degradation rate of hyaluronan following infusion of formulations comprising rHuPH20 will dynamically alter the resistance to fluid flow.…”

Section: Discussion and Outlookmentioning

confidence: 99%

SubQ-Sim: A Subcutaneous Physiologically Based Biopharmaceutics Model. Part 1: The Injection and System Parameters

Pepin,

Grant,

Wood

2023

Pharm Res

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Purpose To construct a detailed mechanistic and physiologically based biopharmaceutics model capable of predicting 1) device-formulation-tissue interaction during the injection process and 2) binding, degradation, local distribution, diffusion, and drug absorption, following subcutaneous injection. This paper is part of a series and focusses on the first aspect. Methods A mathematical model, SubQ-Sim, was developed incorporating the details of the various substructures within the subcutaneous environment together with the calculation of dynamic drug disposition towards the lymph ducts and venous capillaries. Literature was searched to derive key model parameters in healthy and diseased subjects. External factors such as body temperature, exercise, body position, food or stress provide a means to calculate the impact of “life events” on the pharmacokinetics of subcutaneously administered drugs. Results The model predicts the tissue backpressure time profile during the injection as a function of injection rate, volume injected, solution viscosity, and interstitial fluid viscosity. The shape of the depot and the concentrations of the formulation and proteins in the depot are described. The model enables prediction of formulation backflow following premature needle removal and the resulting formulation losses. Finally, the effect of disease (type 2 diabetes) or the presence of recombinant human hyaluronidase in the formulation on the injection pressure, are explored. Conclusions This novel model can successfully predict tissue back pressure, depot dimensions, drug and protein concentration and formulation losses due to incorrect injection, which are all important starting conditions for predicting drug absorption from a subcutaneous dose. The next article will describe the absorption model and validation against clinical data.

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Section: Discussion and Outlookmentioning

confidence: 99%

SubQ-Sim: A Subcutaneous Physiologically Based Biopharmaceutics Model. Part 1: The Injection and System Parameters

Pepin,

Grant,

Wood

2023

Pharm Res

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“…Two models using COMSOL Multiphysics simulated injection into skin and tumors. The skin injection model evaluated solution motion after injection, albeit without momentum ignoring more rigorous considerations [19]. This model evaluated tissue deformation following solute injection and its impact thereof on porosity and fluid flow, each affecting solute diffusion, advection, and adsorption.…”

Section: Clinical Backgroundmentioning

confidence: 99%

Convection-enhanced diffusion and directed withdrawal of methylene blue in agarose hydrogel using finite element analyses

Shaw

Hossain

Riviere-Cazaux

et al. 2022

Preprint

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Precision drug delivery for optimized therapeutic targeting requires knowledge of momentum transport and molecular diffusion of molecules within the patient's interstitial tissue, especially for tumor treatment within the brain. Dispersion in the interstitial space is impacted by delivery method, tissue material properties, individual-specific fluid flow, and particle size of the input solute. Knowledge of a drug's dispersion allows for optimizing solute delivery, concentration, and flow rates to maximize drug distribution and biomarker recovery. For delivering drugs, increased knowledge of drug location after delivery can improve therapeutic treatment by optimizing the dosing of healthy and unhealthy tissue. Finite element methods (FEM) tools, such as COMSOL Multiphysics, can simulate molecular distribution inside -individual specific shapes and porous material properties. Furthermore, an additional unmet need is delivery methods that can be adjusted to manipulate diffusion regions through tissue via techniques such as directed flow. This would be especially valuable in targeted drug delivery within tumors to increase the cancerous surface area covered while limiting damage to surrounding tissues. In this project, the directed flow was induced by perfusing the injected solution at an input probe while withdrawing fluid at an output probe, enabling targeted flow through the desired region. FEM computation faithfully replicated these conditions and could be used to determine the effective concentrations perfused over the region of interest. We leveraged COMSOL Multiphysics to perform a computational study simulating convection-enhanced delivery (CED) with an output probe pulling the concentration profile over the region of interest. This simulation system can be applied to therapeutics targeting, vaccine subcutaneous injection, and waste and media diffusion in tissue engineering.

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“…However, these models focus on the material response and fluid pressure change in interstitial tissue, and do not model the changes of fluid pressures in blood vessels and lymphatic vessels or the drug transport induced by the material responses. Drug transport coupled with tissue deformation is also considered in some studies (Han et al., 2021 ; Hou et al., 2021 ; Zheng et al., 2021a ; Leng et al., 2022 ; Rahimi et al., 2022 ). Nevertheless, these studies apply a linear model to describe the lymphatic uptake assuming that the lymphatic fluid pressure is constant, and ignore changes in lymphatic pressure due to tissue deformation and fluid flow.…”

Section: Introductionmentioning

confidence: 99%

MPET ² : a multi-network poroelastic and transport theory for predicting absorption of monoclonal antibodies delivered by subcutaneous injection

Wang

Leng

et al. 2023

Drug Delivery

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Subcutaneous injection of monoclonal antibodies (mAbs) has attracted much attention in the pharmaceutical industry. During the injection, the drug is delivered into the tissue producing strong fluid flow and tissue deformation. While data indicate that the drug is initially uptaken by the lymphatic system due to the large size of mAbs, many of the critical absorption processes that occur at the injection site remain poorly understood. Here, we propose the MPET 2 approach, a multi-network poroelastic and transport model to predict the absorption of mAbs during and after subcutaneous injection. Our model is based on physical principles of tissue biomechanics and fluid dynamics. The subcutaneous tissue is modeled as a mixture of three compartments, i.e., interstitial tissue, blood vessels, and lymphatic vessels, with each compartment modeled as a porous medium. The proposed biomechanical model describes tissue deformation, fluid flow in each compartment, the fluid exchanges between compartments, the absorption of mAbs in blood vessels and lymphatic vessels, as well as the transport of mAbs in each compartment. We used our model to perform a high-fidelity simulation of an injection of mAbs in subcutaneous tissue and evaluated the long-term drug absorption. Our model results show good agreement with experimental data in depot clearance tests.

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Multiphysics Modeling and Simulation of Subcutaneous Injection and Absorption of Biotherapeutics: Model Development

Cited by 19 publications

References 89 publications

SubQ-Sim: A Subcutaneous Physiologically Based Biopharmaceutics Model. Part 1: The Injection and System Parameters

SubQ-Sim: A Subcutaneous Physiologically Based Biopharmaceutics Model. Part 1: The Injection and System Parameters

Convection-enhanced diffusion and directed withdrawal of methylene blue in agarose hydrogel using finite element analyses

MPET ² : a multi-network poroelastic and transport theory for predicting absorption of monoclonal antibodies delivered by subcutaneous injection

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Multiphysics Modeling and Simulation of Subcutaneous Injection and Absorption of Biotherapeutics: Model Development

Cited by 19 publications

References 89 publications

SubQ-Sim: A Subcutaneous Physiologically Based Biopharmaceutics Model. Part 1: The Injection and System Parameters

SubQ-Sim: A Subcutaneous Physiologically Based Biopharmaceutics Model. Part 1: The Injection and System Parameters

Convection-enhanced diffusion and directed withdrawal of methylene blue in agarose hydrogel using finite element analyses

MPET 2 : a multi-network poroelastic and transport theory for predicting absorption of monoclonal antibodies delivered by subcutaneous injection

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MPET ² : a multi-network poroelastic and transport theory for predicting absorption of monoclonal antibodies delivered by subcutaneous injection