Levodopa Pharmacokinetic Optimization by Metal Coordination

描述（由申请人提供）：Synthonics正在开发金属配位左旋多巴药物产品MCP-311，以获得FDA批准。左旋多巴作为帕金森病（PD）患者的主要药物治疗已有40年，并且仍然具有独特的有效性。然而，通过施用标准制剂中的左旋多巴来代替多巴胺导致脉动递送，其特征在于血浆曲线中的一系列峰和谷。血浆中左旋多巴的优化分布可以通过连续多巴胺能递送（CDD）来实现，以提供对大脑黑质纹状体通路的更自然的连续多巴胺能刺激（CDS）。在使用Duodopa（Abbott）的患者中可以观察到CDD的获益。随着输注样稳定的血浆左旋多巴水平，运动并发症的发生率降低，并在狭窄的治疗窗口内维持血浆药物水平。对于提供类似于肠输注提供的血浆分布的口服施用的左旋多巴产品存在未满足的临床需求。除了改善晚期患者的治疗结果外，从药物治疗开始提供CDD对于避免以后的运动并发症具有很大的希望。有人推测，避免脉冲输送可能会减缓PD的进展。Synthonics发现，铋与左旋多巴形成稳定的配位络合物，形成MCP-311中的活性成分次多巴酸铋。Synthonics在动物中进行的初步口服研究的数据与以下假设一致，即这种新的分子实体粘附在肠活性吸收部位上游的胃粘膜上，形成药物贮库，当胃酸作用于化合物时，左旋多巴从该贮库中逐渐释放。Synthonics试图利用其金属配位化学来控制左旋多巴从该贮库中的释放，以在口服产品中提供CDD。Synthonics建议开发MCP-311作为PD症状的治疗方法。研究计划旨在获取数据以支持505（B）（2）研究性新药申请。一旦进入临床开发，MCP-311将与Sinemet-CR进行左旋多巴比较，并与Devrom TM（次没食子酸铋）（一种OTC内部除臭剂）进行铋暴露比较。临床前开发将包括4个具体目标。首先，微调分析方法和控制，开发cGMP合成并准备临床试验材料。其次，开发一种处方，以优化分散，从而允许原料药在体内聚合。第三，在先进的动物模型中进行药理学研究，以表征相关的药代动力学并优化制剂。第四，利用这些研究结果制定临床计划。最终目标是市场上一个简单可靠的左旋多巴口服产品，提供显着的和实际的临床效益。 公共卫生相关性：本项目是一项药物开发项目，旨在1）开发一种用于人体给药的次多巴酸铋口服混悬液制剂，2）进行并完成支持MCP-311（一种金属配位药物（MCP）新药）的研究性新药申请（IND）所需的化学、生产和控制以及非临床研究。口服给药后，次多巴酸铋混悬液旨在涂覆胃并形成聚合物膜，其用作药物递送储库以随时间连续释放左旋多巴，并通过在延长的时间段内维持稳态治疗全身左旋多巴浓度为帕金森病患者提供连续的多巴胺能递送（CDD）。与公共卫生的相关性表现为更好的帕金森病药物治疗形式，通过使用MCP方法作为工具，从口服左旋多巴产品实现更连续的输注样药物递送，解决了未满足的CDD医疗需求。

DESCRIPTION (provided by applicant): Synthonics is developing the metal-coordinated levodopa drug product, MCP-311, for FDA approval. Levodopa has served as a primary pharmacotherapy for patients with Parkinson's disease (PD) for 40 years and it remains uniquely effective. However, replacing dopamine by administering levodopa in a standard formulations results in pulsatile delivery, characterized by a series of peaks and troughs in the plasma profile. Optimized profiles for levodopa in plasma can be achieved with continuous dopaminergic delivery (CDD) to provide a more natural continuous dopaminergic stimulation (CDS) of the brain's nigrostriatal pathway. The benefits of CDD can be observed in patients using Duodopa (Abbott). With infusion-like steady plasma levodopa levels comes a decreased incidence of motor complications and maintenance of plasma drug levels within a narrowing therapeutic window. There is an unmet clinical need for an orally administered levodopa product that provides plasma profiles similar to that provided by intestinal infusion. In addition to improving therapeutic outcomes in late stage patients, providing CDD from the beginning of drug therapy holds great promise for avoiding motor complications later. Some speculate that avoiding pulsatile delivery may slow the progression of PD. Synthonics found that bismuth forms a stable coordination complex with levodopa to form bismuth subdopate, the active ingredient in MCP-311. Synthonics' data from pilot oral studies in animals are consistent with the hypothesis that this new molecular entity adhered to the stomach lining upstream of the intestinal active absorption sites, forming a drug depot from which levodopa was released gradually as gastric acids acted on the compound. Synthonics seeks to use its metal coordinated chemistry to control the release of levodopa from this depot to provide CDD in an orally administered product. Synthonics proposes to develop MCP-311 as a treatment for the symptoms of PD. The research plan is designed to acquire data to support a 505(b)(2) investigational new drug application. Once in clinical development, MCP-311 will be compared with Sinemet-CR for levodopa and with DevromTM (bismuth subgallate), an OTC internal deodorant, for bismuth exposure. The preclinical development will consist of 4 specific aims. First, to fine tune analytical methods and controls, develop a cGMP synthesis and prepare clinical trial material. Second, to develop a formulation to optimize dispersion to allow for in vivo polymerization of the drug substance. Third, to perform pharmacology studies in an advanced animal model to characterize the relevant pharmacokinetics and optimize formulation. Fourth, to use the results of these studies to develop a clinical plan. The ultimate goal is to market a simple and reliable levodopa oral product to provide significant and practical clinical benefits. PUBLIC HEALTH RELEVANCE: This project is a drug development program designed to 1) develop an oral suspension formulation of bismuth subdopate for human administration and 2) conduct and complete the chemistry, manufacturing and controls and nonclinical studies required to support an Investigational New Drug application (IND) for MCP-311, a metal-coordinated pharmaceutical (MCP) new drug product. After oral administration, the bismuth subdopate suspension is intended to coat the stomach and form a polymeric film that serves as drug delivery depot to release levodopa continuously over time, and provide a continuous dopaminergic delivery (CDD) for Parkinson's disease patients through maintenance of steady state therapeutic systemic levodopa concentrations over an extended time period. The relevance to public health comes in the form of a better drug therapy for Parkinson's disease that addresses the unmet medical need for CDD by using the MCP approach as a tool to achieve a more continuous infusion-like drug delivery from an orally administered levodopa product.