Stent elution rate determines drug deposition and receptor-mediated effects
Drug eluting stent designs abound and yet the dependence of efficacy on drug dose and elution duration remains unclear. We examined these issues within a mathematical framework of arterial drug distribution and receptor binding following stent elution. Model predictions that tissue content linearly...
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| Format: | Article |
| Language: | en_US |
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Elsevier
2016
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| Online Access: | http://hdl.handle.net/1721.1/102303 https://orcid.org/0000-0002-7832-7156 |
| _version_ | 1826208674511585280 |
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| author | Tzafriri, Abraham R. Groothuis, Adam Price, G. Sylvester Edelman, Elazer R. |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Tzafriri, Abraham R. Groothuis, Adam Price, G. Sylvester Edelman, Elazer R. |
| author_sort | Tzafriri, Abraham R. |
| collection | MIT |
| description | Drug eluting stent designs abound and yet the dependence of efficacy on drug dose and elution duration remains unclear. We examined these issues within a mathematical framework of arterial drug distribution and receptor binding following stent elution. Model predictions that tissue content linearly tracks stent elution rate were validated in porcine coronary artery sirolimus-eluting stents implants. Arterial content varied for stent types, progressively declining from its Day 1 peak and tracking with rate-limiting drug elution — near zero-order release was three-fold more efficient at depositing drug in the stented lesion than near first-order release. In vivo data were consistent with an overabundance of non-specific sirolimus-binding sites relative to the specific receptors and to the delivered dose. The implication is that the persistence time of receptor saturation and effect is more sensitive to duration of elution than to eluted amount. Consequently, the eluted amount should be sufficiently high to saturate receptors at the target lesion, but dose escalation alone is an inefficient strategy for prolonging the duration of sirolimus deposition. Moreover, receptor saturating drug doses are predicted to be most efficacious when eluted from stents in a constant zero order fashion as this maximizes the duration of elution and receptor saturation. |
| first_indexed | 2024-09-23T14:09:52Z |
| format | Article |
| id | mit-1721.1/102303 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:09:52Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1023032022-09-28T18:58:14Z Stent elution rate determines drug deposition and receptor-mediated effects Tzafriri, Abraham R. Groothuis, Adam Price, G. Sylvester Edelman, Elazer R. Harvard University--MIT Division of Health Sciences and Technology Tzafriri, Abraham R. Edelman, Elazer R. Drug eluting stent designs abound and yet the dependence of efficacy on drug dose and elution duration remains unclear. We examined these issues within a mathematical framework of arterial drug distribution and receptor binding following stent elution. Model predictions that tissue content linearly tracks stent elution rate were validated in porcine coronary artery sirolimus-eluting stents implants. Arterial content varied for stent types, progressively declining from its Day 1 peak and tracking with rate-limiting drug elution — near zero-order release was three-fold more efficient at depositing drug in the stented lesion than near first-order release. In vivo data were consistent with an overabundance of non-specific sirolimus-binding sites relative to the specific receptors and to the delivered dose. The implication is that the persistence time of receptor saturation and effect is more sensitive to duration of elution than to eluted amount. Consequently, the eluted amount should be sufficiently high to saturate receptors at the target lesion, but dose escalation alone is an inefficient strategy for prolonging the duration of sirolimus deposition. Moreover, receptor saturating drug doses are predicted to be most efficacious when eluted from stents in a constant zero order fashion as this maximizes the duration of elution and receptor saturation. National Institutes of Health (U.S.) (RO1 GM-49039) Cordis Corporation 2016-04-28T12:35:17Z 2016-04-28T12:35:17Z 2012-05 2012-02 Article http://purl.org/eprint/type/JournalArticle 01683659 http://hdl.handle.net/1721.1/102303 Tzafriri, Abraham R., Adam Groothuis, G. Sylvester Price, and Elazer R. Edelman. “Stent Elution Rate Determines Drug Deposition and Receptor-Mediated Effects.” Journal of Controlled Release 161, no. 3 (August 2012): 918–926. https://orcid.org/0000-0002-7832-7156 en_US http://dx.doi.org/10.1016/j.jconrel.2012.05.039 Journal of Controlled Release Creative Commons Attribution-Noncommercial-NoDerivatives http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Tzafriri, Abraham R. Groothuis, Adam Price, G. Sylvester Edelman, Elazer R. Stent elution rate determines drug deposition and receptor-mediated effects |
| title | Stent elution rate determines drug deposition and receptor-mediated effects |
| title_full | Stent elution rate determines drug deposition and receptor-mediated effects |
| title_fullStr | Stent elution rate determines drug deposition and receptor-mediated effects |
| title_full_unstemmed | Stent elution rate determines drug deposition and receptor-mediated effects |
| title_short | Stent elution rate determines drug deposition and receptor-mediated effects |
| title_sort | stent elution rate determines drug deposition and receptor mediated effects |
| url | http://hdl.handle.net/1721.1/102303 https://orcid.org/0000-0002-7832-7156 |
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