Corbett, Jennifer M. and Hawthorne, Ian and Coulter, Ivan S. and English, Karen (2021) Drug delivery formulation impacts cyclosporine efficacy in a humanised mouse model of acute graft versus host disease. Transplant Immunology, 65. p. 101373. ISSN 0966-3274

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Abstract

Acute graft versus host disease (aGvHD) is an allogeneic T cell mediated disease which manifests as a severe inflammatory disease affecting multiple organs including the liver, skin, lungs and gastrointestinal tract. Existing prophylactic and therapeutic approaches in aGvHD include the use of cyclosporine A (CyA), however the currently approved CyA formulations which were designed to optimise systemic CyA bioavailability can have a number of side effects including nephrotoxicity as well as the potential to attenuate the beneficial Graft-versus-Leukemia (GvL) effect. An added complication with CyA is that it has a narrow therapeutic window, and following oral administration is absorbed only from the small intestine, with variable cytochrome P450 metabolism contributing to intra- and inter-patient variability. This study sought to investigate the efficacy of a novel CyA oral formulation enabled by the integrated SmPill® oral drug delivery platform in a humanised mouse model of aGvHD. The study compared the approved optimised CyA (Neoral®) with SmPill®-enabled CyA and a systemic intravenous CyA formulation. Our findings clearly demonstrate superior efficacy of the novel SmPill® CyA in prolonging survival in a clinically relevant humanised aGvHD model. SmPill® CyA significantly reduced pathological score in the small intestine, colon, liver and lung of aGvHD mice. In addition, SmPill® CyA significantly reduced the levels of pro-inflammatory cytokines in all the GvHD target tissues examined. Notably, SmPill® CyA was significantly more potent in reducing GvHD associated pathology and inflammatory cytokine production compared to the optimised approved oral CyA formulation, Neoral®.

Item Type:	Article
Keywords:	Graft versus host disease; Cyclosporine; Immunosuppression; Drug formulation; Drug delivery; Humanised mouse model;
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Human Health Institute
Item ID:	17042
Identification Number:	https://doi.org/10.1016/j.trim.2021.101373
Depositing User:	Karen English
Date Deposited:	20 Mar 2023 14:05
Journal or Publication Title:	Transplant Immunology
Publisher:	Elsevier
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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