Indwelling Biosensor for real-time chemotherapeutic blood level monitoring

 描述（由申请人提供）：本II期SBIR提案的具体目的是开发一种基于导管的生物传感器，用于监测药物输注期间的化疗药物血液水平。本II期包括器械临床试验的IDE提交。实时监测血液水平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），并可能最大限度地提高疗效。我们最初的目标治疗药物是阿霉素。多柔比星是一种常用的化学治疗剂，其使用受到剂量相关的心脏毒性的限制（Swain等人，2002; Legha等人，1982年）。所提出的装置允许监测与心脏组织损伤相关的多柔比星峰值血液水平和累积暴露（Desoize和Robert，1994）。在某种程度上，由于个体间的药代动力学可变性，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）和峰值血液浓度方面可能具有五倍的变化（Eksborg等人，1985年）。此外，我们将开发类似的伊马替尼传感器作为该II期提案的一部分，因为伊马替尼暴露是高度时间依赖性的，并且血浆水平与毒性相关（Eechoute等人，2012; Widmer等人，2008年）。在I期（1 R43 HL 126473）中，我们展示了一种基于导管的多柔比星生物传感器，其生理相关动态范围为10 nM-10 uM，在血液中稳定读数>8小时。该装置将在化疗输注前几分钟插入患者静脉，并将在输注前、输注期间和输注后连续测量药物水平。现有的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，通常排除了非研究环境中的药代动力学指导治疗。我们的设备将使个体PK监测成为可能，并且在大多数情况下，在药物治疗期间的常规基础上负担得起。关于用氟尿嘧啶进行药代动力学指导治疗的研究已经证明了改善的客观反应，产生了更高存活率的趋势，并且在转移性结肠直肠患者中导致更少的3/4级毒性（Gamelin et al.，2008年）。所提出的装置将允许这种监测成为常规。在第一阶段，我们表明，我们可以检测血液中的生理相关的阿霉素浓度>8小时，使用一个原型的临床可实施的导管设计，静脉输液。为了将其商业化 为了将传感器产品用于临床，我们需要将我们的设备转化为可扩展的、符合FDA标准的制造工艺，并在体内验证传感器功能。成功与否将通过在器械中证明24小时的体内感知来确定，该器械采用能够以每件器械15美元的价格生产2，600件/月的工艺制造。拟议的工作将最终提交FDA IDE。

 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.