Investigation of Drug Delivery in Rats via Subcutaneous Injection: Case Study of Pharmacokinetic Modeling of Suspension Formulations

Chiang, Po‐Chang; Nagapudi, Karthik; Fan, Peter W.; Liu, Jia

doi:10.1016/j.xphs.2018.06.003

Cited by 10 publications

(15 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hence, a change in the route of drug administration would be a powerful strategy to overcome its limitations (Solari et al, 2017 ; Gao et al, 2021 ). According to the literature, SC administration is a popular alternative delivery route as it provides the following advantages, such as (1) potential to avoid enteral metabolism and liver first-pass effect and to promote the effective delivery of drugs that have low oral bioavailability; (2) potential to achieve improved tolerability by minimizing the peak to trough ratio in the systemic circulation; (3) potential to achieve prolonged systemic exposure (Chiang et al, 2019 ; Lee et al, 2019 ). Therefore, it is necessary to verify whether different administration of immunosuppression influences outcomes.…”

Section: Discussionmentioning

confidence: 99%

Immunosuppressive effect of PLGA-FK506-NPs in treatment of acute cardiac rejection via topical subcutaneous injection

Deng

Jin

et al. 2021

Drug Delivery

View full text Add to dashboard Cite

FK506, a first-line immunosuppressant, is routinely administered orally and intravenously to inhibit activation and proliferation of T cells after heart transplantation (HT). Current administration route is not conducive enough to exert its efficacy in lymphatic system. Herein, we proposed that subcutaneous (SC) administration of FK506-loaded nanoparticles (PLGA-FK506-NPs) would be valuable for treating acute rejection after HT. The biodistribution and pharmacokinetic study revealed that it could effectively deliver FK506 to the lymph nodes (LNs) due to their suitable particle size, especially in inguinal LNs. Subsequently, the therapeutic efficacy of PLGA-FK506-NPs on the HT model was evaluated using intravenous (IV), intragastric (IG), or SC injection. Histopathological analysis revealed that 80% of allografts exhibited only grade 1R rejection with negligible lymphocyte infiltration in the SC group. The IV group exhibited 40% 1R rejection with mild lymphocyte infiltration and 20% grade 3R that require further intervention, and the IG group exhibited grades 40% 3R rejection with more lymphocyte infiltration. Moreover, the infiltration of T cells and the secretion of IL-2 and IFN-γ were significantly reduced in the SC group compared with the IG or IV group. The mean survival time (MST) further revealed that 50% of grafts treated with PLGA-FK506-NPs via SC injection survived longer than IG and IV groups. Moreover, the MST of single-dose SC injection of PLGA-FK506-NPs demonstrated that it would effectively reduce the required dose for a similar therapeutic effect. Overall, these results indicate that SC administration of PLGA-FK506-NPs is a more effective route for chronic FK506 treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Immunosuppressive effect of PLGA-FK506-NPs in treatment of acute cardiac rejection via topical subcutaneous injection

Deng

Jin

et al. 2021

Drug Delivery

View full text Add to dashboard Cite

show abstract

“…Chiang et al developed a series of un-milled and milled suspensions for SC administration and conducted rat PK studies. 52 The data of the average plasma concentration of griseofulvin from 0 to 24 h were extracted from Figure 6 in their study using Origin 2018 (OriginLab Corporation, Northampton, MA, USA). 52 2.7.2.…”

Section: Release Profile Modeling Using Statistical and Machine Learn...mentioning

confidence: 99%

Development of an In Vitro System To Emulate an In Vivo Subcutaneous Environment: Small Molecule Drug Assessment

Lou

Hageman

2022

Mol. Pharmaceutics

View full text Add to dashboard Cite

A reliable in vitro system can support and guide the development of subcutaneous (SC) drug products. Although several in vitro systems have been developed, they have some limitations, which may hinder them from getting more engaged in SC drug product development. This study sought to develop a novel in vitro system, namely, Emulator of SubCutaneous Absorption and Release (ESCAR), to better emulate the in vivo SC environment and predict the fate of drugs in SC delivery. ESCAR was designed using computer-aided design (CAD) software and fabricated using the three-dimensional (3D) printing technique. ESCAR has a design of two acceptor chambers representing the blood uptake pathway and the lymphatic uptake pathway, respectively, although only the blood uptake pathway was investigated for small molecules in this study. Via conducting a DoE factor screening study using acetaminophen solution, the relationship of the output (drug release from the “SC” chamber to the “blood circulation” chamber) and the input parameters could be modeled using a variety of methods, including polynomial equations, machine learning methods, and Monte Carlo simulation-based methods. The results suggested that the hyaluronic acid (HA) concentration was a critical parameter, whereas the influence of the injection volume and injection position was not substantial. An in vitro–in vivo correlation (IVIVC) study was developed using griseofulvin suspension to explore the feasibility of applying ESCAR in formulation development and bioequivalence studies. The developed LEVEL A IVIVC model demonstrated that the in vivo PK profile could be correlated with the in vitro release profile. Therefore, using this model, for new formulations, only in vitro studies need to be conducted in ESCAR, and in vivo studies might be waived. In conclusion, ESCAR had important implications for research and development and quality control of SC drug products. Future work would be focused on further optimizing ESCAR and expanding its applications via assessing more types of molecules and formulations.

show abstract

“…Although subcutaneous administration is widely used for the delivery of therapeutic products, a reliable model for the absorption of drugs administrated by the subcutaneous injection is lacking. 9 The mechanisms of drug absorption in subcutaneous tissue are quite complex which relates to lymphatics, interstitium, blood capillaries, and also cells and extracellular matrices (ECMs). It is commonly believed that there are two primary approaches for systemic absorption.…”

Section: Introductionmentioning

confidence: 99%

Transport and Lymphatic Uptake of Biotherapeutics Through Subcutaneous Injection

Han

Rahimi

Aramideh

et al. 2022

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

Investigation of Drug Delivery in Rats via Subcutaneous Injection: Case Study of Pharmacokinetic Modeling of Suspension Formulations

Cited by 10 publications

References 26 publications

Immunosuppressive effect of PLGA-FK506-NPs in treatment of acute cardiac rejection via topical subcutaneous injection

Immunosuppressive effect of PLGA-FK506-NPs in treatment of acute cardiac rejection via topical subcutaneous injection

Development of an In Vitro System To Emulate an In Vivo Subcutaneous Environment: Small Molecule Drug Assessment

Transport and Lymphatic Uptake of Biotherapeutics Through Subcutaneous Injection

Contact Info

Product

Resources

About