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Predicting Transdermal Fentanyl Delivery Using Mechanistic Simulations for Tailored Therapy

Transdermal drug delivery is a key technology for administering drugs. However, most devices are “one-size-fits-all”, even though drug diffusion through the skin varies significantly from person-to-person. For next-generation devices, personalization for optimal drug release would benefit from an au...

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Autores principales: Defraeye, Thijs, Bahrami, Flora, Ding, Lu, Malini, Riccardo Innocenti, Terrier, Alexandre, Rossi, René M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550783/
https://www.ncbi.nlm.nih.gov/pubmed/33117179
http://dx.doi.org/10.3389/fphar.2020.585393
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author Defraeye, Thijs
Bahrami, Flora
Ding, Lu
Malini, Riccardo Innocenti
Terrier, Alexandre
Rossi, René M.
author_facet Defraeye, Thijs
Bahrami, Flora
Ding, Lu
Malini, Riccardo Innocenti
Terrier, Alexandre
Rossi, René M.
author_sort Defraeye, Thijs
collection PubMed
description Transdermal drug delivery is a key technology for administering drugs. However, most devices are “one-size-fits-all”, even though drug diffusion through the skin varies significantly from person-to-person. For next-generation devices, personalization for optimal drug release would benefit from an augmented insight into the drug release and percutaneous uptake kinetics. Our objective was to quantify the changes in transdermal fentanyl uptake with regards to the patient’s age and the anatomical location where the patch was placed. We also explored to which extent the drug flux from the patch could be altered by miniaturizing the contact surface area of the patch reservoir with the skin. To this end, we used validated mechanistic modeling of fentanyl diffusion, storage, and partitioning in the epidermis to quantify drug release from the patch and the uptake within the skin. A superior spatiotemporal resolution compared to experimental methods enabled in-silico identification of peak concentrations and fluxes, and the amount of stored drug and bioavailability. The patients’ drug uptake showed a 36% difference between different anatomical locations after 72 h, but there was a strong interpatient variability. With aging, the drug uptake from the transdermal patch became slower and less potent. A 70-year-old patient received 26% less drug over the 72-h application period, compared to an 18-year-old patient. Additionally, a novel concept of using micron-sized drug reservoirs was explored in silico. These reservoirs induced a much higher local flux (µg cm(-2) h(-1)) than conventional patches. Up to a 200-fold increase in the drug flux was obtained from these small reservoirs. This effect was mainly caused by transverse diffusion in the stratum corneum, which is not relevant for much larger conventional patches. These micron-sized drug reservoirs open new ways to individualize reservoir design and thus transdermal therapy. Such computer-aided engineering tools also have great potential for in-silico design and precise control of drug delivery systems. Here, the validated mechanistic models can serve as a key building block for developing digital twins for transdermal drug delivery systems.
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spelling pubmed-75507832020-10-27 Predicting Transdermal Fentanyl Delivery Using Mechanistic Simulations for Tailored Therapy Defraeye, Thijs Bahrami, Flora Ding, Lu Malini, Riccardo Innocenti Terrier, Alexandre Rossi, René M. Front Pharmacol Pharmacology Transdermal drug delivery is a key technology for administering drugs. However, most devices are “one-size-fits-all”, even though drug diffusion through the skin varies significantly from person-to-person. For next-generation devices, personalization for optimal drug release would benefit from an augmented insight into the drug release and percutaneous uptake kinetics. Our objective was to quantify the changes in transdermal fentanyl uptake with regards to the patient’s age and the anatomical location where the patch was placed. We also explored to which extent the drug flux from the patch could be altered by miniaturizing the contact surface area of the patch reservoir with the skin. To this end, we used validated mechanistic modeling of fentanyl diffusion, storage, and partitioning in the epidermis to quantify drug release from the patch and the uptake within the skin. A superior spatiotemporal resolution compared to experimental methods enabled in-silico identification of peak concentrations and fluxes, and the amount of stored drug and bioavailability. The patients’ drug uptake showed a 36% difference between different anatomical locations after 72 h, but there was a strong interpatient variability. With aging, the drug uptake from the transdermal patch became slower and less potent. A 70-year-old patient received 26% less drug over the 72-h application period, compared to an 18-year-old patient. Additionally, a novel concept of using micron-sized drug reservoirs was explored in silico. These reservoirs induced a much higher local flux (µg cm(-2) h(-1)) than conventional patches. Up to a 200-fold increase in the drug flux was obtained from these small reservoirs. This effect was mainly caused by transverse diffusion in the stratum corneum, which is not relevant for much larger conventional patches. These micron-sized drug reservoirs open new ways to individualize reservoir design and thus transdermal therapy. Such computer-aided engineering tools also have great potential for in-silico design and precise control of drug delivery systems. Here, the validated mechanistic models can serve as a key building block for developing digital twins for transdermal drug delivery systems. Frontiers Media S.A. 2020-09-29 /pmc/articles/PMC7550783/ /pubmed/33117179 http://dx.doi.org/10.3389/fphar.2020.585393 Text en Copyright © 2020 Defraeye, Bahrami, Ding, Malini, Terrier and Rossi http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Defraeye, Thijs
Bahrami, Flora
Ding, Lu
Malini, Riccardo Innocenti
Terrier, Alexandre
Rossi, René M.
Predicting Transdermal Fentanyl Delivery Using Mechanistic Simulations for Tailored Therapy
title Predicting Transdermal Fentanyl Delivery Using Mechanistic Simulations for Tailored Therapy
title_full Predicting Transdermal Fentanyl Delivery Using Mechanistic Simulations for Tailored Therapy
title_fullStr Predicting Transdermal Fentanyl Delivery Using Mechanistic Simulations for Tailored Therapy
title_full_unstemmed Predicting Transdermal Fentanyl Delivery Using Mechanistic Simulations for Tailored Therapy
title_short Predicting Transdermal Fentanyl Delivery Using Mechanistic Simulations for Tailored Therapy
title_sort predicting transdermal fentanyl delivery using mechanistic simulations for tailored therapy
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550783/
https://www.ncbi.nlm.nih.gov/pubmed/33117179
http://dx.doi.org/10.3389/fphar.2020.585393
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