Levodopa Pharmokinetic Optimization by Metal Coordination

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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.