Stent elution rate determines drug deposition and receptor-mediated effects
Author(s)Tzafriri, Abraham R.; Groothuis, Adam; Price, G. Sylvester; Edelman, Elazer R.
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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.
DepartmentHarvard University--MIT Division of Health Sciences and Technology
Journal of Controlled Release
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.
Author's final manuscript