Levodopa Pharmokinetic Optimization by Metal Coordination

描述（由申请人提供）：Synthonics对将金属配位化学应用于多巴胺前体左旋多巴感兴趣。这种生化药物作为帕金森病（PD）患者的主要对症药物治疗已有40年，并且仍然具有独特的有效性。新出现的证据表明，通过施用标准速释制剂中的左旋多巴来代替多巴胺导致脉冲式递送，这可能在严重并发症的发展中起作用，严重并发症通常在3-5年内开始。晚期PD患者通常需要将血浆药物水平维持在狭窄的治疗窗口内，以避免与高药物水平相关的运动障碍，以及当水平低时发生的关闭期。这可以通过生物相容的左旋多巴金属配合物来实现。由于左旋多巴的吸收受限和快速代谢，配制左旋多巴的连续释放版本是困难的。虽然像恩他卡朋、卡比多巴和司来吉兰这样的药物有助于抑制代谢，但延长吸收阶段受到位于小肠近端部分的活性转运蛋白的依赖性的限制。真实的需要一种实用的口服左旋多巴产品，其提供稳定、连续的血液水平，类似于在输注中观察到的水平。除了改善晚期患者的治疗结果外，从药物治疗开始给予左旋多巴以维持持续的多巴胺能刺激对于完全避免这些并发症具有很大的希望。我们公司一直在制造金属配位药物（MCP），为调节药物的药代动力学（PK）提供有效的技术。在大鼠研究中，MCP已被证明对甲状腺激素（T3和T4）、呋塞米和现在的左旋多巴的PK产生有利影响。在此，我们建议证明通过FDA 505（B）（2）途径快速开发潜在先导药物的可行性，并将其开发为具有潜在价值的药物产品。该研究计划涉及设计、合成和纯化一组约50种左旋多巴复合物，其中含有一个镁、钙或锌原子和一个辅助分子，以增强吸收。佐剂包括氨基酸、糖、脂质和抗氧化剂。评价这些MCP将涉及经颈静脉插管大鼠经口给药，并在3小时内采集5次血样。来自这些样本的血浆[将通过LC/MS/MS进行分析]，并将左旋多巴水平对时间作图。显示有利的PK特性的复合物将在II期研究中开发，最终目标是销售一种简单的左旋多巴产品，可以提供显着的临床益处。 公共卫生相关性：这项研究将最终测试这一假设，即实际的连续多巴胺能刺激帕金森氏症患者可以通过金属配位化学完成。我们提出，可以使用金属和佐剂来改变左旋多巴的药代动力学（PK），并允许通过肠道和血液的药物吸收的替代途径，提供一个延长的吸收阶段。此外，这项研究将使我们更好地了解如何将这些技术普遍应用于药物PK的调节，以优化用于治疗各种疾病的药物的治疗结果。

DESCRIPTION (provided by applicant): Synthonics is interested in applying metal coordination chemistry to the dopamine precursor levodopa. This biochemical has served as the primary symptomatic pharmacotherapy for patients with Parkinson's disease (PD) for 40 years and it remains uniquely effective. Emerging evidence suggests that replacing dopamine by administering levodopa in a standard immediate release formulation results in pulsatile delivery which may play a role in the development of serious complications that frequently begin within 3-5 years. Later stage PD victims often experience a need to maintain plasma drug levels within a narrowing therapeutic window in order to avoid dyskinesias, associated with high drug levels, and off periods that occur when levels are low. This may be accomplished with biocompatible metal complexes of levodopa. Formulating a continuous release version of levodopa is difficult due to its restricted absorption and quick metabolism. While drugs like entacapone, carbidopa and selegiline help to inhibit metabolism, extending the absorption phase is limited by a dependence on active transport proteins located in the proximal section of the small intestine. There is a real need for a practical oral levodopa product that provides steady, continuous blood levels similar to those observed with infusions. In addition to improving therapeutic outcomes in late stage patients, administering levodopa so as to maintain continuous dopaminergic stimulation from the beginning of drug therapy holds great promise for avoiding these complications altogether. Our company has been making metal coordinated pharmaceuticals (MCPs) that afford an effective technology for modulating the pharmacokinetics (PK) of drugs. In rat studies, MCPs have been proven to favorably impact the PK of thyroid hormones (T3 and T4), furosemide and now, levodopa. Herein we propose to demonstrate the feasibility of identifying potential lead drugs that will be developed quickly, through an FDA 505(b)(2) pathway, into a potentially valuable drug product. The research plan involves designing, synthesizing and purifying a set of ~50 levodopa complexes with one Mg, Ca or Zn atom and an adjuvant molecule for enhanced absorption. Adjuvants include amino acids, sugars, lipids and antioxidants. Evaluating these MCPs will involve oral dosing in jugular-catheterized rats and sampling blood 5 times over 3 hours. Plasma from these samples [will be analyzed by LC/MS/MS] and the levodopa levels will be plotted against time. Complexes that display favorable PK properties will be developed in Phase II studies leading to an IND. The ultimate goal is to market a simple levodopa product that could provide significant clinical benefits. PUBLIC HEALTH RELEVANCE: This research will ultimately test the hypothesis that practical continuous dopaminergic stimulation for Parkinson's patients can be accomplished through metal coordination chemistry. We propose that a prolonged absorption phase can be provided using metals and adjuvants to modify levodopa's pharmacokinetics (PK) and allow alternate pathways of drug absorption through the intestines and into the blood. Moreover, this study will provide us with a greater understanding of how to apply these techniques generally for the modulation of drug PK in order to optimize therapeutic outcome for drugs that are used to treat a variety of diseases.