Levodopa Pharmokinetic Optimization by Metal Coordination

描述（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。40年来，这种生物化学疗法一直是帕金森病（PD）患者的主要对症药物治疗方法，并且仍然非常有效。新出现的证据表明，在标准的立即释放配方中，用左旋多巴代替多巴胺会导致搏动给药，这可能在3-5年内经常开始的严重并发症的发展中起作用。晚期PD患者通常需要在一个狭窄的治疗窗口内维持血浆药物水平，以避免与高药物水平相关的运动障碍，以及低水平时出现的停运期。这可以通过左旋多巴的生物相容性金属配合物来实现。由于左旋多巴吸收受限，代谢迅速，所以很难研制出一种持续释放的左旋多巴。虽然恩他卡彭、卡比多巴和斯来吉兰等药物有助于抑制代谢，但由于依赖于位于小肠近端部分的活性转运蛋白，延长吸收期受到限制。确实需要一种实用的口服左旋多巴产品，它能提供稳定、持续的血液水平，类似于输液时观察到的水平。除了改善晚期患者的治疗结果外，从药物治疗开始就给予左旋多巴以保持持续的多巴胺能刺激，对于完全避免这些并发症有很大的希望。我公司一直致力于生产金属配位药物（mcp），为调节药物的药代动力学（PK）提供了有效的技术。在大鼠研究中，MCPs已被证明对甲状腺激素（T3和T4）、速尿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)途径识别潜在先导药物的可行性，这些先导药物将被快速开发成具有潜在价值的药物产品。研究计划包括设计、合成和纯化一组约50个左旋多巴配合物，其中含有一个Mg、Ca或Zn原子和一个辅助分子，以增强吸收。佐剂包括氨基酸、糖、脂类和抗氧化剂。评估这些mcp将涉及在颈静脉导管大鼠中口服给药，并在3小时内抽取5次血液。这些样品的血浆[将通过LC/MS/MS分析]，左旋多巴水平将随时间绘制。显示出良好PK特性的复合物将在II期研究中开发，从而获得IND。最终目标是将一种简单的左旋多巴产品推向市场，从而提供显著的临床益处。

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.