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，申请FDA批准。40年来，左旋多巴一直是帕金森病（PD）患者的主要药物治疗方法，至今仍具有独特的疗效。然而，用标准配方的左旋多巴代替多巴胺会导致脉动性给药，其特点是在血浆谱中出现一系列波峰和波谷。通过持续多巴胺能传递（CDD）可以优化血浆中左旋多巴的分布，为大脑黑质纹状体通路提供更自然的连续多巴胺能刺激（CDS）。在使用杜多帕（雅培）的患者中可以观察到CDD的益处。输液样的稳定血浆左旋多巴水平降低了运动并发症的发生率，并在缩小的治疗窗口内维持血浆药物水平。口服左旋多巴产品的血浆谱与肠内输注的血浆谱相似，临床需求尚未得到满足。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有很大的希望。一些人推测，避免搏动分娩可能会减缓PD的进展。合成发现，铋与左旋多巴形成稳定的配位配合物，形成MCP-311的活性成分亚多巴酸铋。Synthonics的初步动物口服研究数据与假设一致，即这种新的分子实体粘附在肠道活性吸收部位上游的胃内膜上，形成一个药物库，当胃酸作用于该化合物时，左旋多巴从该药物库中逐渐释放出来。Synthonics试图利用其金属配合化学来控制左旋多巴从该仓库的释放，以提供口服给药产品中的CDD。Synthonics建议开发MCP-311作为PD症状的治疗药物。该研究计划旨在获取数据，以支持505(b)(2)研究性新药申请。一旦进入临床开发阶段，MCP-311将与用于左旋多巴的Sinemet-CR和用于铋暴露的非处方内部除臭剂DevromTM（次没食子酸铋）进行比较。临床前开发将包括4个具体目标。首先，调整分析方法和控制，开发cGMP合成和制备临床试验材料。第二，开发一种配方以优化分散以允许原料药的体内聚合。第三，在先进的动物模型上进行药理学研究，以表征相关的药代动力学并优化配方。第四，利用这些研究的结果制定临床计划。最终目标是将一种简单可靠的左旋多巴口服产品推向市场，以提供显着和实用的临床效益。

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.