Indwelling Biosensor for real-time chemotherapeutic blood level monitoring

 描述(由申请人提供)：这项第二阶段SBIR提案的具体目标是开发一种基于导管的生物传感器，用于监测药物输注过程中的化疗血液水平。该第二阶段包括提交给我们的设备进行临床测试的集成开发环境。实时监测血药浓度的能力将有助于在狭窄的治疗范围内给药，以最大限度地减少毒副作用(通常是心脏毒性)，并有可能使疗效最大化。我们最初的靶向治疗药物是阿霉素。阿霉素是一种常用的化疗药物，其使用受到与剂量相关的心脏毒性的限制(Swain等人，2002年；Legha等人，1982年)。建议的设备允许监测阿霉素峰值血药浓度和累积暴露，这与心脏组织损伤有关(Desoize和Robert，1994)。在某种程度上，由于个体间的药代动力学差异，避免心脏毒性是困难的--接受相同剂量的个体在曲线下面积(AUC)和峰值血药浓度(AUC)和峰值血药浓度方面可能有五倍的差异(Eksborg等人，1985年)。此外，我们将开发一种类似的伊马替尼传感器作为该第二阶段提案的一部分，因为伊马替尼的暴露高度依赖于时间，而且血浆浓度与毒性相关(Eechoute等人，2012年；Widmer等人，2008年)。在第一阶段(1R43HL126473)，我们展示了一种基于导管的阿霉素生物传感器，其生理动态范围为10 nm-10uM，在血液中8小时内读数稳定。该设备将在化疗输液前几分钟插入患者的静脉，并将持续测量输液前、输液中和输液后的药物水平。现有繁琐的抽血和实验室分析方法来监测患者的药物血液水平，通常排除了在非研究环境中进行药代动力学指导治疗的可能性。我们的设备将使个人PK监测成为可能，并且在几乎任何环境下的药物治疗期间都是负担得起的。药物动力学指导下的氟尿嘧啶治疗研究显示，在转移性结直肠癌患者中，客观反应改善，存活率更高，3/4级毒性更少(Gamelin等人，2008年)。这一拟议的设备将使这种监测成为常规。在第一阶段，我们展示了我们可以使用临床可实施的静脉输液导管设计的原型，在8小时内检测血液中与生理相关的阿霉素浓度。为了将其商业化 为了将我们的产品用于临床，我们需要将我们的设备转换为可扩展的、符合FDA标准的制造工艺，并在体内验证传感器功能。成功与否将通过在每台设备上进行24小时的体内传感演示来确定，该设备的制造工艺能够每月生产2600台设备，每台设备15美元。拟议的工作将在FDA的IDE提交中达到顶峰。

 DESCRIPTION (provided by applicant): The Specific Aim of this Phase II SBIR proposal is to develop a catheter-based biosensor for monitoring chemotherapeutic blood levels during drug infusion. This Phase II includes an IDE submission for clinical testing of our device. The ability to monitor blood levels in real-time will facilitate drug dosing within a narrow therapeutic range o minimize toxic side effects (commonly cardiotoxicity) and potentially maximize efficacy. Our initial target therapeutic agent is doxorubicin. Doxorubicin is a commonly used chemotherapeutic whose use is limited by dose-related cardiotoxicity (Swain et al., 2002; Legha et al., 1982). The proposed device allows for monitoring of doxorubicin peak blood levels and cumulative exposure, which are correlated to heart tissue damage (Desoize and Robert, 1994). In part, avoidance of cardiotoxicity is difficult due to inter-individual pharmacokinetic variabiliy - individuals receiving the same dose may have a five-fold variation in area-under- curve (AUC) and peak blood concentrations (Eksborg et al., 1985). Additionally, we will develop a similar imatinib sensor as part of this Phase II proposal as imatinib exposure is highly time dependent and plasma levels are correlated to toxicities (Eechoute et al., 2012; Widmer et al., 2008). In Phase I (1R43HL126473), we demonstrated a catheter-based biosensor for doxorubicin with a physiologically relevant dynamic range of 10nM - 10uM with a stable readout in blood for >8 hours. This device will be inserted into a patient's vein a few minutes prior to a chemo infusion, and will continuously measure drug levels prior to, during, and post infusion. The burdensome existing method of blood draws and lab analysis to monitor patient drug blood levels generally precludes pharmacokinetically guided treatment in a non-research setting. Our device will make individual PK monitoring possible and affordable on a routine basis during drug treatment in most any setting. Studies on pharmacokinetically guided treatment with fluorouracil have demonstrated improved objective response, produced a trend towards higher survival rate, and resulted in fewer grade 3/4 toxicities in metastatic colorectal patients (Gamelin et al., 2008). Th proposed device will allow such monitoring to be routine. In Phase I we showed that we could detect physiologically relevant doxorubicin concentrations for >8 hrs in blood using a prototype of a clinically implementable catheter design for IV fluid delivery. In order to commercialize this product for clinical use, we need to translate our device to a scalable, FDA-compliant manufacturing process and validate sensor functionality in vivo. Success will be determined by demonstrating in vivo sensing for 24 hours in devices manufactured by a process capable of producing 2,600 units/month at $15 per device. The proposed work will culminate in an FDA IDE submission.