Levodopa Pharmacokinetic Optimization by Metal Coordination

通过金属配位优化左旋多巴药代动力学

• 批准号: 8511517
• 负责人: Thomas Piccariello
• 金额: $ 85.52万
• 依托单位: SYNTHONICS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511517
• 关键词: Acids; Address; Animal Model; Animals; Applications Grants; Area; Bismuth; Blood; Brain; Chemistry; Clinical; Clinical Trials; Complex; Continuous Infusion; Cyclic GMP; Data; Deodorants; Development; Development Plans; Doctor of Medicine; Dopamine; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Evaluation; Excipients; Feces; Film; Gastric Acid; Goals; Human; Incidence; Infusion procedures; Intestines; Investigational New Drug Application; Levodopa; Macaca fascicularis; Maintenance; Marketing; Medical; Metals; Methods; Modeling; Molecular; Monkeys; Monograph; Motor; Oral; Oral Administration; Outcome; Parkinson Disease; Particle Size; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Pharmacy (field); Phase; Plasma; Powder Diffraction; Process; Program Development; Property; Protocols documentation; Public Health; Raman Spectrum Analysis; Research; Research Design; Roentgen Rays; Safety; Series; Shapes; Sinemet; Site; Small Intestines; Staging; Stomach; Suspension substance; Suspensions; Symptoms; Techniques; Testing; Therapeutic; Time; Urine; Work; absorption; analytical method; base; commercialization; controlled release; design; drug development; improved; in vivo; method development; nigrostriatal pathway; phase 1 study; polymerization; pre-clinical; programs; tool

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.

描述（由申请人提供）：Synthonics 正在开发金属配位左旋多巴药品 MCP-311，以供 FDA 批准。 40 年来，左旋多巴一直作为帕金森病 (PD) 患者的主要药物疗法，并且仍然具有独特的疗效。然而，通过在标准制剂中施用左旋多巴来代替多巴胺会导致脉冲式递送，其特征是血浆曲线中出现一系列峰和谷。通过连续多巴胺能输送 (CDD) 可以实现血浆中左旋多巴的优化分布，从而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)。使用 Duodopa (Abbott) 的患者可以观察到 CDD 的益处。通过像输注一样稳定的血浆左旋多巴水平，可以降低运动并发症的发生率，并在缩小的治疗窗内维持血浆药物水平。对于口服左旋多巴产品的临床需求尚未得到满足，该产品提供与肠输注相似的血浆分布。除了改善晚期患者的治疗结果外，从药物治疗一开始就提供 CDD 有望避免以后的运动并发症。一些人推测，避免脉冲输送可能会减缓帕金森病的进展。 Synthonics 发现铋与左旋多巴形成稳定的配位络合物，形成亚掺杂铋，这是 MCP-311 中的活性成分。 Synthonics 在动物试验中获得的口服研究数据与这一假设相一致，即这种新的分子实体粘附在肠道活性吸收位点上游的胃壁上，形成一个药物库，当胃酸作用于该化合物时，左旋多巴逐渐从该库中释放出来。 Synthonics 试图利用其金属配位化学来控制左旋多巴从该储库中的释放，从而在口服产品中提供 CDD。 Synthonics 提议开发 MCP-311 作为 PD 症状的治疗方法。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 将与左旋多巴的 Sinemet-CR 以及铋暴露的 OTC 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，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，开发一种制剂来优化分散，以允许药物在体内聚合。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配方。第四，利用这些研究的结果来制定临床计划。最终目标是销售一种简单可靠的左旋多巴口服产品，以提供显着且实用的临床益处。