Balakrishnan Brinda, Dooley John F, Kopia Gregory, Edelman Elazer R
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
J Control Release. 2007 Nov 6;123(2):100-8. doi: 10.1016/j.jconrel.2007.06.025. Epub 2007 Jul 5.
Millions of patients worldwide have received drug-eluting stents to reduce their risk for in-stent restenosis. The efficacy and toxicity of these local therapeutics depend upon arterial drug deposition, distribution, and retention. To examine how administered dose and drug release kinetics control arterial drug uptake, a model was created using principles of computational fluid dynamics and transient drug diffusion-convection. The modeling predictions for drug elution were validated using empiric data from stented porcine coronary arteries. Inefficient, minimal arterial drug deposition was predicted when a bolus of drug was released and depleted within seconds. Month-long stent-based drug release efficiently delivered nearly continuous drug levels, but the slow rate of drug presentation limited arterial drug uptake. Uptake was only maximized when the rates of drug release and absorption matched, which occurred for hour-long drug release. Of the two possible means for increasing the amount of drug on the stent, modulation of drug concentration potently impacts the magnitude of arterial drug deposition, while changes in coating drug mass affect duration of release. We demonstrate the importance of drug release kinetics and administered drug dose in governing arterial drug uptake and suggest novel drug delivery strategies for controlling spatio-temporal arterial drug distribution.
全球数百万患者接受了药物洗脱支架以降低支架内再狭窄风险。这些局部治疗药物的疗效和毒性取决于动脉内药物的沉积、分布和滞留情况。为了研究给药剂量和药物释放动力学如何控制动脉药物摄取，利用计算流体动力学原理和瞬态药物扩散 - 对流建立了一个模型。使用来自置入支架的猪冠状动脉的经验数据对药物洗脱的建模预测进行了验证。当一团药物在数秒内释放并耗尽时，预测动脉药物沉积效率低下且极少。基于支架的长达一个月的药物释放有效地提供了几乎持续的药物水平，但药物呈现速率缓慢限制了动脉药物摄取。只有当药物释放速率和吸收速率匹配时摄取才达到最大化，这发生在长达一小时的药物释放过程中。在增加支架上药物量的两种可能方法中，调节药物浓度对动脉药物沉积量有显著影响，而包衣药物质量的变化影响释放持续时间。我们证明了药物释放动力学和给药剂量在控制动脉药物摄取方面的重要性，并提出了用于控制动脉药物时空分布的新型给药策略。
