Intravascular drug release kinetics dictate arterial drug deposition, retention, and distribution
Introduction
Blood flow through atherosclerotic vessels is restored by balloon angioplasty and/or stent implantation, but vessel patency is frequently short-lived. In a process termed intimal hyperplasia, proliferating cells grow radially inward to re-occlude the vessel, which results in a clinical failure phenomena termed restenosis. The burden of restenosis has been alleviated in part by delivering anti-proliferative drugs to the arterial wall. The biologic effect of drug therapy is known to be determined by the drug biologic potency [1] and physicochemical properties [2], [3], [4]. However, the role of dosage and timing of arterial drug presentation for biologic outcome remains unclear. Clinical studies have hinted toward the importance of exceeding a dose and/or timing threshold to achieve biologic effect. In the O-SIRIS trial, orally delivered sirolimus inhibited intimal hyperplasia only if administered at high doses for 2 days prior to the procedure [5]. In the ELUTES clinical trial [6], paclitaxel delivered from stents significantly reduced the percent diameter stenosis at 6 months only when delivered at the highest applied drug dose. That biologic success could be achieved by vastly different drug delivery modalities, such as oral delivery [5], drug release from coated stents [7], [8] or coated angioplasty balloons [9], suggests that a range of drug dosage and release kinetics is capable of eliciting the desired arterial response.
Based on both clinical and in vitro data, our hypothesis was that applied drug dose and release kinetics modulate arterial drug uptake. In turn, drug distribution and retention within the arterial wall likely dictate biologic outcome. In an era in which anti-proliferative outcome must be balanced with the risk of potentially fatal toxic sequelae, such as stent thrombosis, understanding how administered dose and release kinetics impact arterial drug uptake is a critical component to ensuring device safety and efficacy. Thus, we examined tissue drug uptake resulting from a range of administered drug dose and release kinetics using computational models. In silico predictions of tissue drug uptake from clinically tested devices were compared with observed in vivo biologic effects. Using this method, we have begun to understand the complex relationships between release kinetics, tissue drug levels, and biologic outcome. As advances in local drug delivery technology enable precisely controlled drug release [10], [11], [12], [13], choosing an effective drug delivery strategy will rely on our knowledge of how different drug delivery modalities achieve a particular arterial drug uptake, which in part dictates biologic effect.
Computational techniques were ideal for this work because they enable rapid consideration of a range of drug doses and release kinetics followed by precise monitoring of arterial drug deposition, distribution, and retention. We employed an experimentally validated finite volume based computational model in which drug diffused from a drug laden strut to and through the arterial wall with simultaneous diffusive–convective drug washout into flowing blood. The computational model predicted that release kinetics and applied drug dose modulate arterial drug deposition, distribution, and retention. But surprisingly, our predicted variations in arterial drug uptake did not necessarily correspond with a dose dependent biologic response. Biologic response is likely determined by device dependent arterial drug uptake and extrinsic factors such as tissue state.
Section snippets
Mathematical model
Drug transport was modeled using a 2-dimensional transient model (Fig. 1). The luminal diameter (2R), 3 mm, was 3 times greater than the arterial wall thickness (Wtissue). The axial distance along the artery was based on the fluid mechanic entry length required to reach fully developed flow [14]. The strut and coating dimensions were based upon representative dimensions of the CYPHER® Sirolimus-eluting Coronary Stent (Cordis Corporation, a Johnson & Johnson Company).
The blood flow was assumed
Release rates are modulated by drug coating diffusivity and affect arterial drug deposition and retention
The validity of the transient 2-dimensional diffusion–convection computational model was confirmed by comparing predicted drug release from stent strut coatings with actual release from devices implanted in porcine coronary arteries. The model accurately predicted in vivo fractional drug release over a 90 day interval with a root mean squared error of < 0.1. In both the model and in vivo experiment, at 2 weeks post-implantation, the stent had released half of its initial load into the tissue and
Discussion
Computational models of drug transport and target penetration are only valid if the simulated release kinetics are realistic. In this study, we demonstrate that a simple Fickian diffusion model of drug transport in the coating can approximate the process wherein drug navigates through a complex porous polymeric coating [21]. This was illustrated when predictions of concentration gradient drug diffusion faithfully matched 30 day in vivo release (Fig. 3A). Although passive diffusion is governed
Conclusions and future directions
Drug release kinetics and applied dose are responsible in part for the duration and magnitude of arterial drug uptake. Surprisingly, the clinical data in conjunction with computational predictions suggest that biologic effect exhibits a threshold response despite wide variations in arterial drug uptake. It is likely that the drug delivery modality and arterial wall jointly contribute to the biologic effect of drugs on vascular repair. Thus, a favorable biologic response to locally delivered
Acknowledgements
The study was supported in part by grants from the NIH (R01 HL-49309) and an unrestricted gift from Cordis Corporation (a Johnson and Johnson Company). We thank Drs. Ajit Mishra, Ramesh Marrey, and Robert Burgermeister (Cordis Corporation) for their assistance in determining representative stent and coating dimensions.
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