Multiscale pharmacokinetic modeling of systemic exposure of subcutaneously injected biotherapeutics

Zheng, Fudan; Hou, Peng; Corpstein, Clairissa D.; Park, Kinam; Li, Tonglei

doi:10.1016/j.jconrel.2021.07.043

Cited by 13 publications

(5 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Due to the absence of experimental data we neglected local degradation of the proteins, and FcRn binding, which may lead to overpredictions of the absorption. The MPET 2 model, when coupled with whole-body PK models, may help understand the impact of local injection conditions on bioavailability, which is significant but remains poorly understood (Zheng et al., 2021b ; Zou et al., 2021 ). This opens the opportunity to understand the effects on drug absorption and bioavailability of parameters such as injected fluid volume, injection flow rate, injection site, and forces applied to the tissue on the drug absorption.…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…It was reported that mAbs with increased positive charge in Fv regions exhibited incrementally enhanced binding to epithelial cell surfaces and cellular uptake [12]. Furthermore, pharmacokinetic modeling of 19 SC administered mAbs revealed that electrostatic charge in the Fv regions substantially influenced SC absorption rate of mAbs [24].…”

Section: Discussionmentioning

confidence: 99%

Predicting Human Bioavailability of Subcutaneously Administered Fusion Proteins and Monoclonal Antibodies

Zou

2023

Preprint

View full text Add to dashboard Cite

There has been an increasing trend towards subcutaneous (SC) delivery of fusion proteins and monoclonal antibodies (mAbs) in recent years versus intravenous (IV) administration. The prediction of bioavailability is one of the major barriers in clinical translation of SC administered therapeutic proteins due to a lack of reliable in vitro and preclinical in vivo predictive models. In this study, we explored the relationships between human SC bioavailability and physicochemical or pharmacokinetic properties of 20 Fc- or albumin-fusion proteins and 98 monoclonal antibodies. An inverse linear correlation was observed between human SC bioavailability and human intravenous clearance (CL) or isoelectric point (pI). The bioavailability of fusion proteins is more correlated with pI while the bioavailability of mAbs is more correlated with CL. A mAbs with intravenous CL < 4 mL/day/kg is likely to have SC bioavailability > 60%. Multivariate regression models were developed using intravenous CL and pI of a training set (N = 59) as independent variables. The predictive models were validated with an independent test set (N = 33). A linear regression model resulted in 27 among 33 (82%) predictions within 0.8- to 1.2-fold deviations. Overall, this study demonstrated that CL- and pI-based multivariate regression models could be used to predict human SC bioavailability of fusion proteins and mAbs.

show abstract

“…The simulated absorption kinetics is further fitted by an exponential function of time ( m LNP = m abs × e K abs × t ) to be numerically integrated with the whole-body PK model. The exponential form was found to be the most accurate among other numerical functions tried . The fitting was conducted using an Origin 2022b instrument (OriginLab Corporation, MA).…”

Section: Methodsmentioning

confidence: 99%

“…Understanding how formulation attributes govern the in vivo exposure of a lipid system is nonetheless limited, making the development of predictive PK models based on formulation properties a considerable challenge. Multiscale pharmacokinetic modeling that builds on bottom-up simulation of local absorption and transport kinetics of injected LNPs offers a promising solution to this challenge and allows one to study the in vivo performance of LNPs with various particle properties . Our previous multiphysics study examined the contribution of formulation attributes and tissue properties to the local absorption kinetics, but the effect on systemic exposure was not explored.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Multiphysics-Informed Pharmacokinetic Modeling of Systemic Exposure of Intramuscularly Injected LNPs

Di,

Wu,

Hou

et al. 2023

Mol. Pharmaceutics

Self Cite

View full text Add to dashboard Cite

Lipid nanoparticle (LNP) constructs have been widely developed for gene therapy delivery. Understanding local absorption and presystemic clearance kinetics of LNPs, however, remains limited. This subsequently restrains the prediction and assessment of the systemic exposure of locally injected LNPs. As such, a multiscale computational approach was developed by integrating multiphysics simulation of intramuscular absorption kinetics of LNPs with whole-body pharmacokinetics modeling, bridged by a presystemic lymphatic kinetic model. The overall framework was enabled by utilizing physiological parameters obtained from the literature and drugrelated parameters derived from experiments. The multiscale modeling and simulation approach predicted the systemic exposure of LNPs administered intramuscularly, with a high degree of agreement between the predicted and the experimental data. Sensitivity analyses revealed that the local absorption rate, pinocytosis presystemic clearance rate, and lymph flow rate of the presystemic lymphatic compartment had the most significant impacts on C max . The study yielded refreshing perspectives on estimating systemic exposures of locally injected LNPs and their safety and effectiveness.

show abstract

Multiscale pharmacokinetic modeling of systemic exposure of subcutaneously injected biotherapeutics

Cited by 13 publications

References 81 publications

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

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

Predicting Human Bioavailability of Subcutaneously Administered Fusion Proteins and Monoclonal Antibodies

Multiphysics-Informed Pharmacokinetic Modeling of Systemic Exposure of Intramuscularly Injected LNPs

Contact Info

Product

Resources

About

Multiscale pharmacokinetic modeling of systemic exposure of subcutaneously injected biotherapeutics

Cited by 13 publications

References 81 publications

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

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

Predicting Human Bioavailability of Subcutaneously Administered Fusion Proteins and Monoclonal Antibodies

Multiphysics-Informed Pharmacokinetic Modeling of Systemic Exposure of Intramuscularly Injected LNPs

Contact Info

Product

Resources

About

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

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